Abstract
The blood-brain barrier (BBB) preserves brain health through selective permeability, and its disruption is a hallmark of many neurological disorders. Mechanical stimuli such as shear stress and cyclic strain are increasingly recognised to influence BBB integrity and function, while alterations in tissue stiffness and extracellular matrix composition contribute to its breakdown during ageing and disease. Despite its importance, BBB mechanobiology remains underexplored. Here we highlight the central role of mechanics in BBB development, pathology, and ageing, identify key knowledge gaps, and argue that combining innovative BBB model systems with mechanical probing techniques could transform therapeutic strategies targeting brain vascular dysfunction.
Similar content being viewed by others
Introduction
A healthy blood–brain barrier (BBB) is essential for maintaining the delicate brain microenvironment and ensures cerebral homoeostasis. Its key function is to allow the selective bidirectional transport of molecules crucial for supporting critical brain functions and blocking the entry of toxins, pathogens, and other blood-derived products1. BBB dysfunction associated with increased BBB permeability has been observed as a consequence of ageing as well as in various neurological conditions, including hypoxic and ischaemic insults, epilepsy, brain tumours, neurodegenerative disorders (such as Parkinson’s and Alzheimer’s disease (AD)), and psychiatric conditions like depression, schizophrenia, and autism spectrum disorder1,2,3,4,5,6,7,8. During BBB dysfunction, emerging evidence suggests that BBB mechanics are altered, which may not be merely incidental but could play an active role in facilitating BBB breakdown. These mechanical changes are a natural part of development and ageing, but are also prominent features of various neuropathologies. While the broader field of mechanobiology has revealed that mechanics impact cell behaviour and tissue morphogenesis, the mechanobiology of the BBB remains an underexplored frontier. With the growing prevalence of neurodegenerative diseases, the BBB’s essential role in preserving neural homoeostasis and its sensitivity to mechanical disturbances demand thorough investigation. In this perspective, we provide comprehensive evidence highlighting the pivotal role of mechanics in normal BBB function while also exploring how mechanical forces and properties influence BBB development, ageing, and disease and what therapeutic opportunities could emerge from these insights.
The blood-brain barrier: An overview
Structurally, the BBB pertains primarily to the systemic capillaries, which are the smallest vessels of the cerebrovascular network (diameter ~3–7 μm, wall thickness ~0.1 μm) and the main location for blood–brain exchange9,10 (Fig. 1b).
a Schematic representation of the BBB. The BBB is located at the brain capillaries and consists of brain microvascular endothelial cells (BMECs), pericytes (PC), and astrocytes (AC). b The BMECs are tightly linked by tight junction (TJ) proteins, thereby limiting non-aqueous paracellular diffusion and facilitating the entry of molecules by different transcellular pathways. During BBB breakdown, the TJ proteins are disrupted, allowing the free entry of blood-derived products into the brain. Created in BioRender. Konig, S. (2025) https://BioRender.com/eqcbpzi. c Cross-sectional scanning electron microscopy (SEM) image of a capillary of a mouse brain, showing a BMEC forming a TJ with itself. PCs and astrocytic end-feet align closely to the BMEC, which is surrounded by the basement membrane (BM). Adapted from Wolburg H, Noell S, Wolburg-Buchholz K, Mack A, Fallier-Becker P, Neuroscientist, pp. 180–193. Copyright © 2009 by Copyright Holder. Reprinted by Permission of Sage Publications177. d Corresponding SEM image of histological sections collected from a recently developed in vitro BBB model showing similar cellular interactions as in vivo, adapted from ref. 178. Stromal cells and the BMEC interact actively (magnified image in the inset), as witnessed by the increased vesicle density at the contact point between the astrocytic end-feet and the BMEC (red arrow).
Three main cell types, including brain microvascular endothelial cells (BMECs), pericytes, and astrocytes9, are primarily responsible for BBB function (Fig. 1a, b). These cells are in turn surrounded by specific extracellular matrix (ECM) components such as a vascular basement membrane and an intraluminal glycocalyx layer as well as a perivascular space that constitutes the glymphatic circulation and is believed to be a critical pathway for the clearance of substances such as amyloid beta from the brain9,11.
BMECs are generally considered to be the core constituting cells of the BBB because of their selective barrier properties12. Being located on the intraluminal side of the capillaries, they form a tight barrier by expressing complex tight junctions composed of proteins, such as claudin 5 (CLDN5), occludin, and the zonula occludens protein 1 (ZO-1), which limit paracellular diffusion and require the majority of large molecule transport to occur through the transcellular pathway12,13 (Fig. 1b). Here, various membrane transporters shuttle molecules passively or actively between the blood and the brain parenchyma14. Since both the tight junctions and the membrane transporters can undergo rapid modulation and regulation, BMECs allow the brain to adapt quickly to changing energy demands and efficiently secrete waste products14. Besides their specific expression profiles, BMECs also differ from peripheral endothelial cells by displaying a higher expression of mitochondrial content, a lack of fenestration, and a low degree of pinocytosis, thereby further complementing the effectiveness and selectivity of this endothelial barrier15,16.
The second type of BBB-associated cells are pericytes, which are embedded in the basement membrane and wrap around BMECs17 (Fig. 1c). They exhibit the highest capillary coverage in neural tissue, covering up to 37% of the extraluminal side of BMECs18. Throughout development and adulthood, pericytes are key players in BBB formation and regulation by actively communicating with BMECs19. Through paracrine and juxtacrine signalling, including “peg-and-socket” contacts, pericytes can induce the expression of BBB-specific genes in BMECs and regulate the number of tight junctions in them19. Importantly, pericyte-deficient animal models have shown regional differences in BBB permeability upon pericyte loss, possibly implicating a heterogenous distribution of pericytes20. Pericytes are also involved in other functions such as the clearance of toxic substances and neurovascular coupling, whereby they contract to alter capillary blood flow depending on the changing energy demands of the corresponding brain region21,22,23.
Astrocytes, the third type of BBB-associated cells, form astrocytic end-feet extensively covering the extraluminal side of BMECs and pericytes18 (Fig. 1c, d). They play a central role in mediating a sufficient supply of nutrients, such as glucose and oxygen, to regions of the brain with high synaptic activity and energy demands24,25. Hereby, astrocytes regulate smooth muscle cells in arterioles to induce vasodilation25. Additionally, they influence the expression and localisation of transporters and enzyme systems in BMECs26. They are also reportedly capable of altering the invasion of circulating cells, including immune and cancer cells, across the BBB. Hereby, astrocytes secrete chemokines and inflammatory cytokines that act on BMECs and change the expression of tight-junction proteins as well as cell adhesion molecules on BMECs, thereby promoting adhesion and transmigration27,28,29,30. It was also shown recently that astrocytes can promote the chemotaxis and chemokinesis of cancer cells directly without affecting vascular permeability31.
The basement membrane is a 20- to 200-nm-thick proteoglycan-rich matrix made of a network formed primarily by collagen IV and laminin isoforms held together by nidogen and perlecan, as well as other proteoglycans and enzymes32,33. While all three cell types form direct cell–cell junctions via proteins such as connexins and cadherins, all the cells are also tightly anchored within this abluminal basement membrane34. Besides its role in anchoring BBB-associated cells, the basement membrane also modulates various signalling mechanisms that are important for BBB function and maintenance. It also constitutes an important barrier limiting the entry or exit of tumour and immune cells35.
Blood-brain barrier mechanobiology
Cells are mechanosensitive. They actively sense and respond to physical cues from their local cellular microenvironment36. Mechanotransduction, the process whereby mechanical signals trigger intracellular or biochemical signalling cascades, has been shown to alter the function and behaviour of various cell types within different pathophysiological processes37,38. A large body of evidence supports the importance of mechanics within the peripheral vasculature39,40,41. Generally, vascular permeability, tone, and inflammatory states are all tightly linked by regulated mechanobiological pathways42,43,44. Impaired mechanotransduction due to stiffened blood vessels and impaired flow patterns is thought to promote the development of cardiovascular diseases such as atherosclerosis45,46. Mechanics also likely plays an essential role at the BBB. However, given its unique architecture and barrier-forming properties, including tight junctions and distinct extracellular matrix (ECM) component expression, it raises the question of whether different mechanisms might be at play47.
Types of mechanical forces involved in BBB functioning
The BBB is the main interface between the blood and the brain. It may, therefore, be exposed to mechanical cues from both the blood flow and the surrounding brain tissue. Cells and matrix components within the BBB also exhibit their own distinct mechanical characteristics. Based on this, we propose that the mechanical cues outlined in the following (summarised in Fig. 2) contribute to the regulation of BBB function.
Top panel: Mechanical cues (grey boxes) acting on the BBB originate from blood flow, the mechanical properties of cells and the surrounding extracellular matrix. Bottom panel: Multiple mechanosensors and signalling pathways in BMECs modulate their ability to maintain a tight barrier. Shear stress is sensed by CD44 at the glycocalyx (GCX) and by VE-cadherin, which activate the RhoA/RAC1 pathway to promote junctional protein localisation at the plasma membrane. In contrast, stretch and other mechanical perturbations to the endothelium are detected by G protein–coupled receptors (GPCRs) and mechanosensitive ion channels (TRPP2 and TRPC1), which can trigger actin stress fibre formation and disrupt tight junction assembly. Further details are discussed in Section 3.2. Created in BioRender. Konig, S. (2025) https://BioRender.com/z8u1cwz.
Shear stress, generated by frictional forces acting parallel to the vessel wall, is key to normal vascular function. The shear stress experienced by the endothelium is inversely proportional to the cube of the vessel radius and directly proportional to viscosity, assuming Poiseuille flow with Newtonian fluid and steady flow conditions48. Direct measurement of shear stress in human brain capillaries is challenging due to the invasive nature of the required procedures. However, shear stress can be predicted from indirect measurements of cerebral blood flow, vessel diameter and blood viscosity, leading to estimates of 1–2 Pa in human brain capillaries48. Direct measurements via intravital imaging of rat brains have revealed highly heterogenous flow patterns with stresses ranging from 0.5 to 2.3 Pa in cerebral capillaries49. Several in vitro studies have previously investigated the positive influence of shear stress on BBB function by applying different shear stress levels ranging from 1.9 × 10-4 to 1.5 Pa50,51,52,53. It is important to note that when comparing the response to mechanical stimuli in different studies, one must consider the specifics of each model system. For instance, cells exposed to shear stress within a polymer microchannel may experience forces that differ significantly from those experienced by cells cultured on transwell membranes or in standard cell culture flasks due to the varying stiffness of the substrates, which can affect the cellular response. Studies have investigated the role of shear stress in different model systems, including under BMEC monoculture and co-culture conditions, and comparative flow vs. no-flow settings39,50,54,55,56,57,58. It was thus shown that physiological shear stress is positively correlated with improved vascular barrier integrity, BMEC survival, and the degree of BMEC alignment to the flow direction. In BMECs, significant changes in the gene expression of tight junction proteins and protective proteins, such as those of the ABC transporter family (including multidrug resistance transporters like P-glycoprotein) and antioxidant enzymes, result from increased shear stress54,59,60. ECM protein production pathways are also enriched54,61. Different studies have investigated the effect of shear stress on BMEC alignment. In contrast to peripheral endothelial cells, which typically align in the direction of flow, BMECs have been observed to align perpendicularly to the flow direction or maintain their cobblestone morphology under shear stress51,58,62,63. Only a few studies have reported BMEC alignment in the flow direction64,65, which may be explained by differences in flow exposure times and variations in the design of the devices used. While shear stress appears to be associated with improved barrier function, it should be noted that an abnormally high shear stress (4 Pa), which may, for example, occur during pathology, has been found to lead to a decrease in the expression of tight junction proteins as well as altered junctional morphology66. Besides shear stress, the intraluminal cyclic pressure within the vasculature, though highly damped at the level of the capillaries, also induces cyclic strain on the BBB. Such physiological cyclic strain was found to decrease BBB permeability and facilitate transport along the vessel wall retrograde to the applied fluid flow67. However, another in vitro study found a decrease in tight junction expression and morphology66. Besides differences in BMEC sources and co-culture methods, the contrasting results of the studies may be attributed to the use of different substrates on which BMECs were cultured, whereby either a hydrogel composed of collagen, hyaluronan and Matrigel67 or a simple silicone tube was used66. These substrates may absorb and transmit the pulsatile forces experienced by the BMECs differently, which could thus explain the discrepancy between the two studies. The distinct effects of shear stress and cyclic strain may also be highly dependent on the specific flow profiles, such as continuous, pulsatile or oscillatory. In peripheral vessels, particularly oscillatory shear (0–4 dyn/cm²) at arterial bifurcations, contributes to endothelial dysfunction and atherosclerosis. This occurs through glycocalyx disruption, cytoskeletal disorganisation68, downregulation of ecNOS, and upregulation of ET-1, leading to inflammation and vasoconstriction69,70. High shear stress (>2 Pa) counteracts these effects by suppressing VEGFA, HIF1, and ANG2, thereby maintaining vascular stability69,71. Differences in shear-related outcomes between the BBB and peripheral vessels may stem from unique shear magnitudes, transcriptional responses (e.g., KLF2 and FOXC2 regulating distinct targets in BBB cells)54,68, and pathological contexts. While peripheral atherosclerosis arises from oscillatory shear-induced ET-1/ROS signalling69,70, BBB dysfunction in conditions like stroke is often linked to abrupt shear loss, triggering MMP-9 and inflammatory cascades47. These differences highlight the importance of BBB-specific shear studies in accounting for unique transcriptional programs and barrier reinforcement mechanisms absent in peripheral models.
In addition to blood pressure and flow rate, the levels of shear stress and cyclic strain are impacted by the vessel radius and geometry and the strength of the vessel wall72. In addition to the vessel diameter, the curvature and bifurcations alter the blood-flow patterns and hence the mechanical forces experienced by the BMECs. In cerebral aneurysms, which occur at larger arteries rather than at the capillary level of the BBB, saccular formations appear predominantly at vessel bifurcations, curved regions and branch points since here hemodynamics are altered73,74. Interestingly, in Alzheimer’s disease (AD), various changes in the vessel geometry, including in microvessels, have been observed, such as vessel fragmentation, branching, and thinning, loop formation, increased vessel tortuosity, and thickening of the vascular basement membrane72,75. In vitro studies suggest that, in areas with disturbed flow due to bifurcations, the barrier permeability is significantly greater compared to regions with undisturbed flow76. Therefore, the geometrical changes observed in AD may alter the vascular flow patterns and the associated mechanical forces, which may contribute to and potentiate AD pathology through BBB breakdown. Multiscale modelling of the impact of traumatic brain injury (TBI) on BBB disruption has highlighted how vessel alignment and directionality in vessel networks determine the mechanical forces impacting the BBB (see Box 1)77.
Brain tissue mechanical properties also impact BBB function1. The brain is one of the softest tissues in the body and its stiffness changes in various neurological diseases78,79,80. Modelling studies investigating the over-pressurisation of arterioles (commonly observed during TBI) showed that the relative difference in stiffness between the arterioles and the surrounding brain tissue determines the degree of strain transmitted to the vessel surroundings81. For the BBB, so far, no direct correlation has been reported between brain tissue stiffness and BBB function. However, during physiological ageing as well as in AD, the brain softens, which in both cases coincides with the breakdown of the BBB80,82.
The macroscopically apparent brain-tissue stiffness emerges from the mechanical properties of its microstructural components, including cells, the ECM, interstitial fluid, and soluble and insoluble molecules, as well as from active or passive interactions amongst them. Because the ECM is the main determinant of brain stiffness, the ECM architecture and stiffness itself are particularly important mechanical cues influencing the BBB. Changes in the BBB matrix composition, which directly impact the ECM stiffness, have previously been observed, for example in ageing, during which changes in the number of tight junctions have also been reported83,84,85. The mechanical properties of the surrounding cells may also impact BMECs and BBB function. Under ischaemic conditions, astrocytic end-feet at the BBB reportedly undergo significant swelling, leading to temporary microvascular obstruction due to compression86. Pericytes, on the other hand, are highly contractile cells that, similar to smooth muscle cells, can alter capillary blood flow in response to the energy demand of the surrounding brain tissue, a process known as neurovascular coupling. Pericyte contraction induces substratum deformation and can thus directly apply a mechanical stimulus to adjacent vascular BMECs or modify the effective mechanical stiffness of the surrounding ECM87. Recent studies have shown that stiffer vessels with decreased vascular compliance are closely linked to pathologies characterised by barrier disruption, including cognitive decline and progression to dementia88. Vascular stiffening not only precedes neurodegenerative changes but also exacerbates amyloid and tau pathology, further compromising BBB integrity. Additionally, arterial stiffening and inflammation have been shown to interactively exacerbate tau pathology in older adults with mild cognitive impairment, highlighting the complex interplay between vascular mechanics and neurodegenerative processes89. These findings underscore the critical role of vascular compliance in maintaining BBB function and suggest that loss of compliance contributes to barrier breakdown in disease states. While in vivo and clinical studies have established strong correlations between vascular stiffness and BBB dysfunction, there remains a significant gap in the field regarding direct in vitro investigations of how matrix stiffness specifically alters tight junctions between cells with endothelial phenotypes. Most current in vitro BBB models have not systematically varied substrate stiffness to directly assess its impact on tight junction protein expression and barrier properties. Addressing this gap will be essential for elucidating the mechanistic links between mechanical cues and BBB integrity, and for developing targeted interventions to preserve barrier function in disease.
Mechanotransduction pathways governing BBB function
Despite the increasingly recognised importance of mechanical forces on BBB function, only a few distinct BBB-linked mechanotransduction pathways have so far been identified (Fig. 2). In particular, the intraluminal glycocalyx layer (GCX) has been highlighted. It was shown that, in the peripheral vasculature, the GCX plays an important role in determining vascular permeability, although the underlying mechanisms remain open to debate90,91. It mediates shear-stress-induced nitric-oxide formation, which is linked to vasodilation and vascular health47,92,93. Interestingly, at the BBB, GCX expression is higher than in the peripheral vasculature, and GCX degradation has been suggested in pathologies such as AD, stroke and TBI as well as during ageing94,95,96,97,98. Shi et al. showed that during ageing and neurodegeneration, the GCX is dysregulated, whereby specifically mucin-domain glycoproteins are disrupted, leading to BBB dysfunction and even brain haemorrhaging in mice98. Notably, in the same study, the authors also showed that restoring mucin-type O-glycan biosynthesis in aged mice improved GCX structure and BBB function98. These findings highlight the critical role of GCX integrity in maintaining BBB function. DeOre et al. recently observed that BMECs actively probe blood flow through the cell surface receptor CD4499. This receptor binds to hyaluronic acid (HA) within the GCX and, in the presence of shear stress, mediates BMECs' barrier function through RhoA/RAC1 signalling99. The cell surface receptor syndecan, which binds to the most abundant glycosaminoglycan in the GCX, heparin sulfate, may also be implicated in the mechanotransduction100. Syndecan 1 has previously been shown to be involved in regulating the arrangement of the cytoskeleton in endothelial cells, even though no direct evidence currently exists for BMECs at the BBB101.
The well-defined junctional mechanosensory complex has also been implicated in endothelial mechanotransduction102. Specifically, the junctional protein VE-cadherin (involved in homotypic cell–cell adhesion) and its binding partners (platelets and endothelial cell adhesion molecule 1 (PECAM-1) and vascular endothelial cell growth factor receptor 2 (VEGF-R2)) have been shown to mediate shear-stress-induced mechanotransduction in BMECs, leading to increased RAC1 and barrier integrity via occludin60.
Mechanosensitive ion channels, such as the transient receptor potential (TRP), are also heavily expressed in the brain microvasculature and are involved in BBB damage in TBI103,104. More specifically, both TRPP2 and TRPC1 were found to modulate nitric oxide production and actin stress fibre formation during stretch-induced injury of BMECs104. Piezo1, another mechanosensitive cation channel, has recently gained interest for its possible role at the BBB. Piezo1 expressed at BMECs has been found to regulate pericyte proliferation during development via NOTCH signalling105. During cerebral infarction, knocking out Piezo1 restored tight junction protein expression by inhibiting the IL6/GPX pathway, accompanied by improved cognitive function. Pharmacological inhibition of Piezo1 during chronic cerebral hypoperfusion also improved BBB disruption and cognitive impairment, further supporting a role for Piezo1 as an important mechanosensor of capillary perfusion106. By applying targeted mechanical forces to a monolayer of BMECs via picosecond laser excitation to glycoprotein-targeted gold nanoparticles (AuNPs), Li et al. recently proposed that mechanical forces can activate the mechanosensitive Ca2+ channels TRPV4 and Piezo1 as well as mechanosensitive GPCRs. In both cases, intracellular Ca2+ levels are increased, resulting in the activation of the ERK1/2 phosphorylation pathway107. This, together with actin polymerisation due to cell membrane deformations, may then result in cytoskeletal rearrangement and contraction. Given the tight regulation of endothelial barrier integrity by the balance between actomyosin contractile forces and the tethering forces generated by cell-cell and cell–ECM interactions, such cytoskeletal contraction results in BBB opening108. Similarly, increased Ca2+ and cytoskeletal contraction were also observed when BMECs were mechanically stimulated by vertically deployed surface acoustic waves109.
Blood–brain barrier mechanics during disease, development and ageing
The potential role of mechanics in BBB development
Mechanics is a fundamental aspect of development and is crucial for healthy tissue and organ morphogenesis110,111. Nonetheless, much remains to be learned of its role in BBB development. During central nervous system (CNS) vascularisation, at approximately embryonic day E 11.5 of the mouse gestation, mesoderm-derived angioblasts coalesce to form the perineural vascular plexus (PNVP) along the neural tube112,113. Following the release of growth factors, such as VEGF, from cells in the neural tube, ECs in the PNVP undergo sprouting angiogenesis and extend towards the ventricles into the developing CNS112,113,114. By capturing signals emitted by the surrounding CNS cells (such as astrocytes, pericytes and neural cells), these sprouts develop barrier properties to form a functional BBB115,116,117,118.
Wingless–Int1 (Wnt) signalling in endothelial cells has been shown to play a key role in regulating angiogenesis and barrier formation, specifically in the brain but not in peripheral tissues118,119. More specifically, during development, astroglia, oligodendrocytes, and neurons express Wnt7a and Wnt7b, which bind to the Frizzled receptor and its coreceptors Lrp5/6, GPR124, and RECK on endothelial cells to induce canonical Wnt signalling120. Since Wnt7a/b signalling through GPR124/RECK is specific to the BBB, Gpr124/Reck agonists have recently been explored as potential neurovascular protective therapeutics to restore BBB function121. Following Wnt signalling and β-catenin stabilisation, endothelial cells acquire BBB-specific characteristics such as reduced paracellular permeability, suppressed transcytosis, induction of specific solute transporter expression, and recruitment of pericytes115,116,117,118. Interestingly, in addition to the well-established role of VEGF signalling in angiogenesis, Wnt signalling is also essential for brain-specific angiogenesis, ensuring that only BBB-specific endothelial cells can penetrate the developing brain122. Recently, it was shown that Wnt7a/b signalling specifically induces the glycosylphosphatidylinositol-anchored matrix metalloproteinase-25 (MMP25) at the tips of endothelial cells, thereby facilitating their migration by cleaving collagen IV chains122. Given the critical role of the Wnt pathway in brain microvasculature formation, it is not surprising that disruption of Wnt signalling during development, as shown in knockout experiments, leads to severe, brain-specific angiogenic defects and haemorrhaging118. Interestingly, we previously demonstrated that the loss of yes-associated protein 1 (YAP1, a known mechanotransducer) in fibroblasts during murine embryonic development also causes haemorrhaging and disrupts vascular morphogenesis in the head at E 11.5, possibly indicating a role of YAP1 in CNS vascularisation and BBB development. Importantly, YAP1 binds to the transcriptional co‑activator, β‑catenin, which is a key regulator of the above-mentioned WNT signalling pathway. YAP1 is one of the best-established factors involved in cellular mechanotransduction, where it acts as a transcriptional coactivator to translate mechanical stimuli into cellular responses123. Collectively, considering the importance of WNT signalling in BBB development and its linkage to YAP1, YAP1 can act as a mechanotransducer during BBB development by interacting with the WNT signalling cascade, providing regulated mechanical cues for vascular morphogenesis. Indeed, we found that upon YAP1 loss in fibroblasts, regions affected by vascular defects in the developing head of the embryo exhibited a 50% reduction in stiffness124. It is also well-established that stiffness patterns arise during brain development, including in the head mesoderm, which are important for instructing neuronal growth and neural crest cell migration, as well as for instructing BBB morphogenesis111,125.
Distinct BBB alterations during healthy ageing may be linked to changes in BBB mechanics
It has long been established that ageing brings about changes in the brain vasculature, including the BBB, and in the surrounding brain environment126,127. While various age-associated pathologies, including neurodegenerative disorders, lead to a dysfunctional BBB, the BBB arguably undergoes distinctive cellular and structural alterations even during healthy ageing126,127. It is not yet fully understood whether the BBB becomes dysfunctional or, instead, adapts to the evolving demands of the ageing brain126. The concept of healthy ageing and its associated changes in the BBB have recently been extensively reviewed126,127,128,129. From a mechanical point of view, it can be presumed that the numerous structural and cellular changes during ageing also impact BBB mechanics, but there is only limited evidence of this at present. During healthy ageing, the peripheral vasculature stiffness increases because of changes to the ECM130,131. This, in turn, causes a rise in systolic blood pressure and widened pulse pressures, which affects the stress imposed on the microvasculature, including the BBB in the brain capillaries131, although to a lesser degree considering the lower pressure and pulsatility there. As outlined in Part 3.1, forces exhibited by blood flow (such as shear stress, cyclic strain, and interstitial flow) reportedly alter the ability of BMECs to form a functional BBB39,50,54,55,56,57,58,66,67. Thus, the increased blood-flow stress imposed on the BBB during ageing may directly impact BMEC function.
Indeed, BMECs, which also undergo senescence during ageing and in ageing-related diseases, display an increased cytoplasmic area in the ageing human white matter and a decreased number of tight junctions in aged rats85,132,133,134. In addition, various transporter proteins, including transporters important for drug delivery, were found to be altered in BMECs during ageing135,136,137,138,139,140. Pericytes may be lost during ageing, which may further impact the microvasculature blood flow because of their important role in neurovascular coupling130,137. A large body of evidence exists for age-related changes in astrocytes including an inflammatory phenotype with an increase in expression of neuroinflammatory genes, increased oxidative metabolism, and altered glutamate regulation during ageing141,142,143,144. It has also been reported that BBB-associated astrocytes show larger end-feet in aged rats85. Previous studies have revealed that astrocyte activation is associated with altered tissue mechanics79,145. Therefore, it is plausible that perivascular astrocytes also alter their tissue mechanics during ageing, which may impact BBB function. Recently, it was shown that a stiffening of the oligodendrocyte progenitor cell (OPC) niche during ageing causes a decrease in OPC proliferation and differentiation via the mechanoresponsive ion channel Piezo1, confirming the importance of stiffness-associated changes during ageing146.
Interestingly, changes in the BBB ECM are especially distinctive during ageing. In the healthy-aged human brain, the BM at the microvasculature thickens considerably126,147. While this could be the response to an increased pulsative blood-flow stress in the periphery, which may be transmitted to the brain capillaries, animal models of ageing that normally do not show an increased systolic blood pressure or a widened pulse pressure also display a thickened cerebral microvasculature148. This morphological change is accompanied by an altered BM composition, with variations in collagen, laminin, nidogen, perlecan and fibronectin, depending on the assessed brain region in humans or animals84,148,149,150,151. These changes may also result from an altered degradation through matrix metalloproteinases (MMPs), which are dysregulated in various vascular and neurological pathologies80,152. A recent study also reported the accumulation of lipid droplets and aggregates on the perivascular side at the microvasculature in aged mice, further showing a potential dysregulated mechanism of ageing at the BBB153. Previous in vitro studies have shown that BMECs actively respond to the surrounding ECM. For instance, altering the ECM secreted by astrocytes and pericytes directly affected barrier integrity in porcine brain capillary endothelial cells154. Furthermore, evidence indicates that specific binding motifs within the ECM can enhance the attachment and tight junction expression of BMECs155. The changes in ECM composition during ageing may alter the BBB tissue stiffness. So far, potential changes in the mechanical properties of the BBB during ageing have not yet been measured. Additionally, changes in ECM stiffness are often associated with changes in hydraulic permeability, which could impact the clearance of disease-causing substances (e.g., amyloid β, α-synuclein, phosphorylated tau) from the brain parenchyma.
BBB mechanics as a therapeutic target
As exemplified in the section “Types of mechanical forces involved in blood–brain barrier functioning” and further discussed in Boxes 1 and 2, the mechanics of the BBB are altered across various neurological disorders. These changes may be viewed as a response to external factors, such as disrupted blood flow, increased pressure, the incorporation of stiff elements like amyloid-beta, or pathological molecular processes affecting BBB cells and the ECM. However, this perspective is overly simplistic. BBB mechanics play an active role in neurological pathologies, where mechanical alterations result from the disease and contribute to its progression. For instance, ischaemic conditions cause astrocytic end-feet to swell, leading to mechanical pressure and microvascular compression, further exacerbating brain ischaemia86. Such insights highlight the potential of mechanobiology-based therapies for neurological disorders affecting the BBB. These therapies could aim to either reduce external mechanical stressors or intervene with targeted strategies. For instance, various clinical investigations have focused on the relationship between arterial hypertension and dementia, including AD, with promising results for antihypertensive therapy156. These positive effects may at least be partly due to the restored capillary flow, thus reversing BBB pathologies, including BMEC activation, altered ECM secretion and BBB breakdown. However, such systemic interventions may not be feasible for all patients. A more targeted approach, such as blocking pericyte contraction in response to amyloid-beta while applying a vasodilator, has been shown to restore capillary flow in rodents, offering a promising strategy for reversing cerebral blood flow disturbances in AD157. As we further explore the mechanical changes at the BBB, mechanobiology will become increasingly important, both as a direct therapeutic target and as a key factor in assessing therapeutic efficacy.
Emerging technologies to investigate BBB mechanobiology
Despite our increasing knowledge about the influence of mechanical cues on BBB function, much remains to be learned. For this, appropriate systems incorporated with suitable probing methods are required. Determining BBB and vascular mechanics in the living human brain would be most relevant, but is challenging as most traditional mechanical tests require contact with tissue samples or vessels for force application and probing, which may risk the health of volunteers158. Therefore, mechanical measurements must either be performed non-invasively or ex vivo on extracted brain samples. Various techniques have been developed to assess brain tissue mechanics. Magnetic resonance elastography (MRE), is a non-invasive method which can determine overall brain-tissue mechanics, but is limited in its inability to assess mechanical heterogeneity between different brain regions159. Ultrasound elastography is another commonly applied clinical technique for determining tissue elasticity, but its neurological application is limited mostly to intraoperative and neonatal use. As the skull attenuates sound waves, imaging is only possible when the brain is accessible during surgery or before the closing of the fontanelles160,161. Tagged magnetic resonance imaging (MRI) has also been applied to obtain quantitative strain measurements of the human brain following controlled skull motion at a sub-injury level162. While all of these techniques have given valuable insights, they are largely limited in their resolution and more targeted approaches suitable for the scale of the BBB are needed. As explained in earlier sections, the BBB is influenced by both the surrounding cell and brain tissue mechanics, as well as mechanical stimuli exerted by the blood flow. Thus, assessing vascular dynamics may provide important insights into mechanical alterations at the BBB during disease. Various techniques have already been clinically evaluated, including transcranial Doppler ultrasound to determine cerebral blood flow163, as well as different MRI techniques (DSC, DCE, ASL, IVIM) to determine specifically the flow dynamics of the brain microvasculature164.
Ex vivo assessment of the human brain vasculature is specifically useful for high-resolution imaging of the intact microvasculature, which cannot be achieved with current clinical techniques in the living human brain. Hierarchical phase-contrast tomography (HiP-CT) has recently been applied to image whole brains from healthy and diseased donors at the micron scale165. Such high-resolution imaging may provide evidence for yet unseen morphological alterations at the microvasculature, which may also indicate altered BBB mechanics. Performing direct mechanical tests ex vivo only offers limited insights, as the brain consists of highly fragile and biphasic tissue with a large quantity of water that escapes naturally or becomes trapped during brain tissue preparations158. In addition, the ultrasoft and highly heterogeneous mechanical properties of the brain further complicate the application of traditional mechanical measurement techniques158.
Animal experiments face similar challenges when applying traditional contact-dependent mechanical tests and are further limited by ethical issues50,158. In addition, the BBB exhibits species-specific mechanobiological differences that challenge the direct translation of animal model findings to human physiology. Structural variations, such as the complexity of tight junctions and efflux transporter expression, significantly impact barrier properties. Human BMECs form more intricate tight junction networks than rodents, influenced by the species-specific expression of claudin-5 and occludin166,167. While porcine models demonstrate higher transendothelial electrical resistance (TEER) than rodents, their permeability remains comparable due to larger EC size168. Differences in P-glycoprotein (P-gp) expression levels further complicate drug permeability assessments, as rodents exhibit higher baseline activity than humans, potentially underestimating drug toxicity in preclinical studies168,169. Besides differences in BMECs, cellular crosstalk and ECM interactions also differ between humans and animals. Human astrocytes secrete unique factors, such as apolipoprotein E (ApoE) and angiopoietin-1 (Ang-1), enhancing BBB tightness more effectively than rodent-derived factors166. Murine pericytes primarily regulate BBB stability through TGF-β signalling, whereas human pericytes engage in broader cytokine interactions, influencing immune cell trafficking166,167. Despite these differences, animal models remain useful for BBB mechanobiology studies, particularly with the use of a cranial window, a technique that replaces part of the skull with a synthetic optical interface170. This technology has been applied to measure tissue elasticity with optical coherence elastography as well as assess capillary blood flow in vivo through techniques such as two-photon microscopy or laser scanning fluorescence confocal microscopy171,172,173.
Combining advanced imaging modalities like magnetic resonance elastography with computational modelling offers a unique opportunity to decode the complex mechanics of the BBB in vivo. As explained in the section “Types of mechanical forces involved in blood–brain barrier functioning”, the mechanical forces experienced by the BBB are largely transmitted by the surrounding soft brain tissue and blood flow, thus involving complex solid/fluid mechanics phenomena. Although the complexity of the vascular network makes traditional fluid–structure interaction methods difficult, poroelasticity-based approaches have recently been successful. For instance, Vardakis et al. developed a patient-specific three-dimensional multiple-network poroelastic theory-based model to investigate the spatio-temporal transport of fluid between the vasculature system, the cerebrospinal and interstitial fluid, and the brain parenchyma174. By applying this model to both patients with mild cognitive decline and healthy individuals, the authors could predict the swelling of the neurovascular unit during disease.
In vitro BBB models are low-cost and increasingly robust, offering a controlled environment that can be inspected at a high spatial and temporal resolution with various mechanical measurement techniques. Some commonly used experimental techniques that may be useful to study BBB tissue mechanics in vitro are summarised in Box 3 and are further explored in another review36. Combining such probing techniques with suitable in vitro models may provide important novel insights. BBB in vitro models have significantly developed over the recent years, with advances in three-dimensional (3D) cell culture, microfluidic systems, and human iPSC technology enabling the creation of complex multicellular models that mimic human BBB physiology and architecture with high fidelity50,175,176. The development and choice of in vitro models for BBB mechanical studies depend critically on the specific study aims. For example, either a 2D or a 3D in vitro BBB model can be used, depending on the chosen probing technique and its requirements for connecting to the model. However, while the ease of assessment is important, relevant insights into BBB mechanics can only be gained by appropriately balancing model simplicity against biomimicry. Figure 3 shows different examples of how BBB mechanics can be investigated and combined with suitable probing methods.
A range of experimental approaches used to investigate mechanical properties and mechanobiology at the BBB and in the surrounding brain, spanning in vivo, ex vivo, and in vitro contexts. In vivo methods enable assessment of whole-brain and cerebrovascular mechanics, as well as high-resolution imaging through cranial windows. In vitro and ex vivo techniques, detailed in Box 3, allow controlled mechanical measurements and manipulation at the cellular and tissue levels. These complementary strategies, combined with advanced molecular techniques and computational modelling, provide a comprehensive framework for studying biomechanics and mechanotransduction across multiple biological scales. For further details on the specific techniques, see Box 3. Elements of this figure are taken from the following references179,180,181,182,183. Adapted from refs. 179,180,182, and reproduced from refs. 181,183. Created in BioRender. Konig, S. (2025) https://BioRender.com/683mj4q.
Conclusions and future directions
In summary, the past few years have increasingly highlighted the importance of mechanical factors in BBB function. Initial studies have now also begun to uncover their role in BBB pathology. While much of the focus has been on blood-flow-mediated forces, the intrinsic mechanical properties of the BBB and the surrounding tissues, as well as the forces generated by cells and transmitted via the ECM, remain to be fully identified and explored.
Several questions are of fundamental importance and should serve as the focus for future investigations:
-
1)
To what degree are the mechanical cues mentioned in the section “Types of mechanical forces involved in blood–brain barrier functioning” essential for healthy BBB function?
-
2)
What further underlying BBB mechanotransduction pathways exist other than the ones mentioned in the section “Mechanotransduction pathways governing BBB function”?
-
3)
Following the evidence given in the section “Blood–brain barrier mechanics during disease, development and ageing”, it is essential that we decipher how mechanical cues and their underlying mechanotransduction pathways change at the BBB in neurological disorders and ageing. Could these be targeted as part of a more comprehensive therapeutic strategy?
To comprehensively explore these topics, future research should integrate recent technological advancements in vascular and brain mechanics assessment with sophisticated biomimetic BBB in vitro models while also prioritising the development of high-resolution, non-invasive tools capable of real-time monitoring of mechanical changes in the BBB under pathological conditions. Unravelling the role of BBB mechanics holds significant promise, as nearly all neurological disorders are associated with vascular dysfunction. A deeper understanding of BBB mechanobiology could provide a transformative framework for redefining neurovascular health and uncovering innovative therapeutic strategies.
Reporting summary
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
References
Nehra, G., Bauer, B. & Hartz, A. M. S. Blood–brain barrier leakage in Alzheimer’s disease: from discovery to clinical relevance. Pharmacol. Ther. 234, 108119 (2022).
Ximerakis, M. et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci. 22, 1696–1708 (2019).
Desai, B. S., Monahan, A. J., Carvey, P. M. & Hendey, B. Blood–brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy. Cell Transplant. 16, 285–299 (2007).
Remy, S. & Beck, H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 129, 18–35 (2005).
Bronger, H. et al. ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood–tumor barrier. Cancer Res. 65, 11419–11428 (2005).
Kealy, J., Greene, C. & Campbell, M. Blood–brain barrier regulation in psychiatric disorders. Neurosci. Lett. 726, 133664 (2020).
Caffrey, T. M., Button, E. B. & Robert, J. Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease. Neural Regen. Res. 16, 2132–2140 (2021).
Lizano, P., Pong, S., Santarriaga, S., Bannai, D. & Karmacharya, R. Brain microvascular endothelial cells and blood–brain barrier dysfunction in psychotic disorders. Mol. Psychiatry 28, 3698–3708 (2023).
Serlin, Y., Shelef, I., Knyazer, B. & Friedman, A. Anatomy and physiology of the blood–brain barrier. Semin. Cell Dev. Biol. 38, 2–6 (2015).
Carrano, A. et al. Neuroinflammation and blood–brain barrier changes in capillary amyloid angiopathy. Neurodegener. Dis. 10, 329–331 (2012).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Yu, Q.-J., Tao, H., Wang, X. & Li, M.-C. Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke. Neural Regen. Res. 10, 1882–1891 (2015).
Pachter, J. S., de Vries, H. E. & Fabry, Z. The blood–brain barrier and its role in immune privilege in the central nervous system. J. Neuropathol. Exp. Neurol. 62, 593–604 (2003).
Daneman, R. & Prat, A. The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412-a (2015).
Villegas, J. C. & Broadwell, R. D. Transcytosis of protein through the mammalian cerebral epithelium and endothelium. II. Adsorptive transcytosis of WGA-HRP and the blood-brain and brain–blood barriers. J. Neurocytol. 22, 67–80 (1993).
Coomber, B. L. & Stewart, P. A. Morphometric analysis of CNS microvascular endothelium. Microvasc. Res. 30, 99–115 (1985).
Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006).
Mathiisen, T. M., Lehre, K. P., Danbolt, N. C. & Ottersen, O. P. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58, 1094–1103 (2010).
Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).
Villaseñor, R. et al. Region-specific permeability of the blood–brain barrier upon pericyte loss. J. Cereb. Blood Flow. Metab. 37, 3683–3694 (2017).
Cai, C. et al. Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proc. Natl Acad. Sci. USA 115, E5796–E5804 (2018).
Kisler, K. et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20, 406–416 (2017).
Mishra, A. et al. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19, 1619–1627 (2016).
Lin, A. L., Fox, P. T., Hardies, J., Duong, T. Q. & Gao, J. H. Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc. Natl Acad. Sci. USA 107, 8446–8451 (2010).
Iadecola, C. The Neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).
Willis, C. L., Leach, L., Clarke, G. J., Nolan, C. C. & Ray, D. E. Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia 48, 1–13 (2004).
Marchetti, D., Li, J. & Shen, R. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res. 60, 4767–4770 (2000).
Westerhof, T. M. et al. Blood–brain barrier remodeling in an organ-on-a-chip device showing Dkk1 to be a regulator of early metastasis. Adv. NanoBiomed. Res. 3, 2200036 (2023).
Muller, W. A. How endothelial cells regulate transmigration of leukocytes in the inflammatory response. Am. J. Pathol. 184, 886–896 (2014).
Abbott, N. J. Astrocyte-endothelial interactions and blood–brain barrier permeability. J. Anat. 200, 629–638 (2002).
Hajal, C. et al. The CCL2-CCR2 astrocyte–cancer cell axis in tumor extravasation at the brain. Sci. Adv. 7, eabg8139 (2021).
Thomsen, M. S., Birkelund, S., Burkhart, A., Stensballe, A. & Moos, T. Synthesis and deposition of basement membrane proteins by primary brain capillary endothelial cells in a murine model of the blood-brain barrier. J. Neurochem. 140, 741–754 (2017).
Dong, L. et al. Neurologic defects and selective disruption of basement membranes in mice lacking entactin-1/nidogen-1. Lab. Investig. 82, 1617–1630 (2002).
Xu, L., Nirwane, A. & Yao, Y. Basement membrane and blood–brain barrier. Stroke Vasc. Neurol. 4, 78–82 (2019).
Liebner, S., Czupalla, C. J. & Wolburg, H. Current concepts of blood–brain barrier development. Int. J. Dev. Biol. 55, 467–476 (2011).
Moeendarbary, E. & Harris, A. R. Cell mechanics: principles, practices, and prospects. WIREs Syst. Biol. Med. 6, 371–388 (2014).
Kolahi, K. S. & Mofrad, M. R. K. Mechanotransduction: a major regulator of homeostasis and development. WIREs Syst. Biol. Med. 2, 625–639 (2010).
Orr, A. W., Helmke, B. P., Blackman, B. R. & Schwartz, M. A. Mechanisms of mechanotransduction. Dev. Cell 10, 11–20 (2006).
Warboys, C. M., Eric Berson, R., Mann, G. E., Pearson, J. D. & Weinberg, P. D. Acute and chronic exposure to shear stress have opposite effects on endothelial permeability to macromolecules. Am. J. Physiol. Heart Circ. Physiol. 298, H1850–H1856 (2010).
Mammoto, A. et al. Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics. Nat. Commun. 4, 1759 (2013).
Huynh, J. et al. Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci. Transl. Med. 3, 112ra22–1ra22ra22 (2011).
Chien, S. Role of shear stress direction in endothelial mechanotransduction. Mol. Cell Biomech. 5, 1–8 (2008).
Glen, K. et al. Modulation of functional responses of endothelial cells linked to angiogenesis and inflammation by shear stress: differential effects of the mechanotransducer CD31. J. Cell. Physiol. 227, 2710–2721 (2012).
Uematsu, M. et al. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am. J. Physiol.-Cell Physiol. 269, C1371–C1378 (1995).
Ku, D. N., Giddens, D. P., Zarins, C. K. & Glagov, S. Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis 5, 293–302 (1985).
Zarins, C. K. et al. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ. Res. 53, 502–514 (1983).
Nian, K., Harding, I. C., Herman, I. M. & Ebong, E. E. Blood–brain barrier damage in ischemic stroke and its regulation by endothelial mechanotransduction. Front. Physiol. 11, 605398 (2020).
Wong, A. et al. The blood–brain barrier: an engineering perspective. Front. Neuroeng. 6, 7 (2013).
Mairey, E. et al. Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier. J. Exp. Med. 203, 1939–1950 (2006).
Oddo, A. et al. Advances in microfluidic blood–brain barrier (BBB) models. Trends Biotechnol. 37, 1295–1314 (2019).
Chavarria, D., Georges, K. A., O’Grady, B. J., Hassan, K. K. & Lippmann, E. S. Modular cone-and-plate device for mechanofluidic assays in transwell inserts. Front. Bioeng. Biotechnol. 13, 1494553 (2025).
Meena, M. et al. A microfluidic in vitro three-dimensional dynamic model of the blood–brain barrier to study the transmigration of immune cells. Brain Sci. 12, 1293 (2022).
Harding, I. C. et al. Developing a transwell millifluidic device for studying blood–brain barrier endothelium. Lab Chip 22, 4603–4620 (2022).
Cucullo, L., Hossain, M., Puvenna, V., Marchi, N. & Janigro, D. The role of shear stress in blood–brain barrier endothelial physiology. BMC Neurosci. 12, 40 (2011).
Santaguida, S. et al. Side by side comparison between dynamic versus static models of blood–brain barrier in vitro: a permeability study. Brain Res. 1109, 1–13 (2006).
Desai, S. Y. et al. Mechanisms of endothelial survival under shear stress. Endothelium 9, 89–102 (2002).
Colgan, O. C. et al. Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress. Am. J. Physiol. Heart Circ. Physiol. 292, H3190–H3197 (2007).
Choublier, N. et al. Exposure of human cerebral microvascular endothelial cells hCMEC/D3 to laminar shear stress induces vascular protective responses. Fluids Barriers CNS 19, 41 (2022).
Cucullo, L., Hossain, M., Tierney, W. & Janigro, D. A new dynamic in vitro modular capillaries-venules modular system: cerebrovascular physiology in a box. BMC Neurosci. 14, 18 (2013).
Walsh, T. G. et al. Stabilization of brain microvascular endothelial barrier function by shear stress involves VE-cadherin signaling leading to modulation of pTyr-occludin levels. J. Cell. Physiol. 226, 3053–3063 (2011).
Santa-Maria, A. R. et al. Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood-brain barrier model. J. Cereb. Blood Flow Metab. 41, 2201–2215 (2021).
DeStefano, J. G., Xu, Z. S., Williams, A. J., Yimam, N. & Searson, P. C. Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs). Fluids Barriers CNS 14, 20 (2017).
Reinitz, A., DeStefano, J., Ye, M., Wong, A. D. & Searson, P. C. Human brain microvascular endothelial cells resist elongation due to shear stress. Microvasc. Res. 99, 8–18 (2015).
Choublier, N. et al. Blood–brain barrier dynamic device with uniform shear stress distribution for microscopy and permeability measurements. Appl. Sci. 11, 5584 (2021).
Moya, M. L. et al. A reconfigurable in vitro model for studying the blood–brain barrier. Ann. Biomed. Eng. 48, 780–793 (2020).
Garcia-Polite, F. et al. Pulsatility and high shear stress deteriorate barrier phenotype in brain microvascular endothelium. J. Cereb. Blood Flow. Metab. 37, 2614–2625 (2017).
Partyka, P. P. et al. Mechanical stress regulates transport in a compliant 3D model of the blood–brain barrier. Biomaterials 115, 30–39 (2017).
Chen, L. et al. Low or oscillatory shear stress and endothelial permeability in atherosclerosis. Front. Physiol. 15, 1432719 (2024).
Zhou, M. et al. Wall shear stress and its role in atherosclerosis. Front. Cardiovasc. Med. 10, 1083547 (2023).
Ziegler, T., Bouzourène, K., Harrison, V. J., Brunner, H. R. & Hayoz, D. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 686–692 (1998).
Buchanan, C. F., Verbridge, S. S., Vlachos, P. P. & Rylander, M. N. Flow shear stress regulates endothelial barrier function and expression of angiogenic factors in a 3D microfluidic tumor vascular model. Cell Adh. Migr. 8, 517–524 (2014).
Klohs, J. An integrated view on vascular dysfunction in Alzheimer’s disease. Neurodegener. Dis. 19, 109–127 (2019).
Meng, H. et al. Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 38, 1924–1931 (2007).
Socci, L., Pennati, G., Gastaldi, D. & Vena, P. Modeling and mechanobiology of cerebral aneurysms. J. Appl. Biomater. Biomech. 6, 63–71 (2008).
Brown, W. R. & Thore, C. R. Review: Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56–74 (2011).
Bouhrira, N. et al. Disturbed flow disrupts the blood–brain barrier in a 3D bifurcation model. Biofabrication 12, 025020 (2020).
Farajzadeh Khosroshahi, S. et al. Multiscale modelling of cerebrovascular injury reveals the role of vascular anatomy and parenchymal shear stresses. Sci. Rep. 11, 12927 (2021).
Pogoda, K. et al. Compression stiffening of brain and its effect on mechanosensing by glioma cells. N. J. Phys. 16, 075002 (2014).
Moeendarbary, E. et al. The soft mechanical signature of glial scars in the central nervous system. Nat. Commun. 8, 14787- (2017).
Hall, C. M., Moeendarbary, E. & Sheridan, G. K. Mechanobiology of the brain in ageing and Alzheimer’s disease. Eur. J. Neurosci. 53, 3851–3878 (2021).
Dagro, A. M. & Ramesh, K. T. A mechanism for injury through cerebral arteriole inflation. Biomech. Model. Mechanobiol. 18, 651–663 (2019).
Hall, C. M. et al. Hippocampus of the APPNL–G–F mouse model of Alzheimer’s disease exhibits region-specific tissue softening concomitant with elevated astrogliosis. Front. Aging Neurosci. 15, 1212212 (2023).
Xi, Y.-P., Gerda Nette, E., West King, D. & Rosen, M. Age-related changes in normal human basement membrane. Mech. Ageing Dev. 19, 315–324 (1982).
Uspenskaia, O., Liebetrau, M., Herms, J., Danek, A. & Hamann, G. F. Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci. 5, 37 (2004).
Bors, L. et al. Age-dependent changes at the blood–brain barrier. A comparative structural and functional study in young adult and middle aged rats. Brain Res. Bull. 139, 269–277 (2018).
Ito, U., Hakamata, Y., Kawakami, E. & Oyanagi, K. Temporary focal cerebral ischemia results in swollen astrocytic end-feet that compress microvessels and lead to focal cortical infarction. J. Cereb. Blood Flow. Metab. 31, 390- (2011).
Lee, S. et al. Pericyte actomyosin-mediated contraction at the cell–material interface can modulate the microvascular niche. J. Phys.: Condens. Matter 22, 194115 (2010).
Yew, B. & Nation, D. A. Initiative ftAsDN. Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia. Brain 140, 1987–2001 (2017).
Clark, A. L. et al. Elevated inflammatory markers and arterial stiffening exacerbate tau but not amyloid pathology in older adults with mild cognitive impairment. J. Alzheimer’s Dis. 80, 1451–1463 (2021).
Weinbaum, S., Cancel, L. M., Fu, B. M. & Tarbell, J. M. The glycocalyx and its role in vascular physiology and vascular related diseases. Cardiovasc. Eng. Technol. 12, 37–71 (2021).
Dull, R. O. & Hahn, R. G. The glycocalyx as a permeability barrier: basic science and clinical evidence. Crit. Care 26, 273 (2022).
Harding, I. C., Mitra, R., Mensah, S. A., Herman, I. M. & Ebong, E. E. Pro-atherosclerotic disturbed flow disrupts caveolin-1 expression, localization, and function via glycocalyx degradation. J. Transl. Med. 16, 364 (2018).
Ebong, E. E., Lopez-Quintero, S. V., Rizzo, V., Spray, D. C. & Tarbell, J. M. Shear-induced endothelial NOS activation and remodeling via heparan sulfate, glypican-1, and syndecan-1. Integr. Biol.6, 338–347 (2014).
Martens, R. J. H., Vink, H., van Oostenbrugge, R. J. & Staals, J. Sublingual microvascular glycocalyx dimensions in lacunar stroke patients. Cerebrovasc. Dis. 35, 451–454 (2013).
Jepsen, C. H. et al. Effect of valproic acid and injury on lesion size and endothelial glycocalyx shedding in a rodent model of isolated traumatic brain injury. J. Trauma Acute Care Surg. 77, 292–297 (2014).
Gonzalez Rodriguez, E. et al. Traumatic brain injury is associated with increased syndecan-1 shedding in severely injured patients. Scand. J. Trauma Resusc. Emerg. Med. 26, 102 (2018).
Hall, A. A. et al Repeated Low Intensity Blast Exposure Is Associated With Damaged Endothelial Glycocalyx And Downstream Behavioral Deficits. Front. Behav. Neurosci. 11, 104 (2017).
Shi, S. M. et al. Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease. Nature 639, 985–994 (2025).
DeOre, B. J., Partyka, P. P., Fan, F. & Galie, P. A. CD44 mediates shear stress mechanotransduction in an in vitro blood–brain barrier model through small GTPases RhoA and Rac1. FASEB J. 36, e22278 (2022).
Zhao, F., Zhong, L. & Luo, Y. Endothelial glycocalyx as an important factor in composition of blood–brain barrier. CNS Neurosci. Ther. 27, 26–35 (2021).
Chaterji, S., Lam, C. H., Ho, D. S., Proske, D. C. & Baker, A. B. Syndecan-1 regulates vascular smooth muscle cell phenotype. PLoS ONE 9, e89824 (2014).
Conway, D. anielE. et al. Fluid shear stress on endothelial cells modulates mechanical tension across VE-Cadherin and PECAM-1. Curr. Biol. 23, 1024–1030 (2013).
Chang, S. L., Huang, W., Mao, X. & Mack, M. L. Ethanol’s effects on transient receptor potential channel expression in brain microvascular endothelial cells. J. Neuroimmune Pharm. 13, 498–508 (2018).
Berrout, J., Jin, M. & O’Neil, R. G. Critical role of TRPP2 and TRPC1 channels in stretch-induced injury of blood–brain barrier endothelial cells. Brain Res. 1436, 1–12 (2012).
Zi, H. et al. Piezo1-dependent regulation of pericyte proliferation by blood flow during brain vascular development. Cell Rep. 43, 113652 (2024).
Xu, F., Xin, Q., Ren, M., Shi, P. & Wang, B. Inhibition of piezo1 prevents chronic cerebral hypoperfusion-induced cognitive impairment and blood brain barrier disruption. Neurochem. Int. 175, 105702 (2024).
Li, X. et al. Mechanobiological modulation of blood–brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles. Nanoscale 15, 3387–3397 (2023).
Kása, A., Csortos, C. & Verin, A. D. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury. Tissue Barriers 3, e974448 (2015).
Hsiao, M.-Y., Liao, D., Xiang, G. & Zhong, P. Intercellular calcium waves and permeability change induced by vertically deployed surface acoustic waves in a human cerebral microvascular endothelial cell line (hCMEC/D3) monolayer. Ultrasound Med. Biol. 49, 1153–1163 (2023).
Gleghorn J. P., Killian M. L. Mechanobiology throughout development. In Mechanobiology in Health and Disease (ed. Verbruggen, S. W.) Ch. 3, 77–98 (Academic Press, 2018).
Barriga, E. H., Franze, K., Charras, G. & Mayor, R. Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo. Nature 554, 523–527 (2018).
Hajal, C., Le Roi, B., Kamm, R. D. & Maoz, B. M. Biology and models of the blood–brain barrier. Annu. Rev. Biomed. Eng. 23, 359–384 (2021).
Langen, U. H., Ayloo, S. & Gu, C. Development and cell biology of the blood–brain barrier. Annu. Rev. Cell Dev. Biol. 35, 591–613 (2019).
Engelhardt, B. & Liebner, S. Novel insights into the development and maintenance of the blood–brain barrier. Cell Tissue Res. 355, 687–699 (2014).
Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).
Dore-Duffy, P. & Cleary, K. Morphology and properties of pericytes. In The Blood–Brain and Other Neural Barriers: Reviews and Protocols (ed. Nag, S.) 49–68 (Humana Press, Totowa, NJ, 2011).
Mizee, M. R. et al. Retinoic acid induces blood–brain barrier development. J. Neurosci. 33, 1660–1671 (2013).
Daneman, R. et al. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl Acad. Sci. USA 106, 641–646 (2009).
Stenman, J. M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008).
America, M. et al. An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates. Cell Rep. 39, 110902 (2022).
Martin, M. et al. Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders. Science 375, eabm4459 (2022).
Schevenels, G. et al. A brain-specific angiogenic mechanism enabled by tip cell specialization. Nature 628, 863–871 (2024).
Panciera, T., Azzolin, L., Cordenonsi, M. & Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 18, 758–770 (2017).
Whisler, J. et al. Emergent mechanical control of vascular morphogenesis. Sci. Adv. 9, eadg9781 (2023).
Koser, D. E. et al. Mechanosensing is critical for axon growth in the developing brain. Nat. Neurosci. 19, 1592–1598 (2016).
Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M. & Erickson, M. A. Healthy aging and the blood–brain barrier. Nat. Aging 1, 243–254 (2021).
Knox, E. G., Aburto, M. R., Clarke, G., Cryan, J. F. & O’Driscoll, C. M. The blood–brain barrier in aging and neurodegeneration. Mol. Psychiatry 27, 2659–2673 (2022).
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).
Mitchell, G. F. et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women. Hypertension 43, 1239–1245 (2004).
Rizzoni, D. et al. Vascular aging and disease of the small vessels. High Blood Press. Cardiovasc. Prev. 26, 183–189 (2019).
Kiss, T. et al. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. GeroScience 42, 429–444 (2020).
Stewart, P. A. et al. A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc. Res. 33, 270–282 (1987).
Ting, K. K. et al. Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models. GeroScience 45, 3307–3331 (2023).
Moinuddin, A., Morley, J. E. & Banks, W. A. Regional variations in the transport of interleukin-1α across the blood–brain barrier in ICR and aging SAMP8 mice. Neuroimmunomodulation 8, 165–170 (2001).
Mooradian, A. D., Morin, A. M., Cipp, L. J. & Haspel, H. C. Glucose transport is reduced in the blood–brain barrier of aged rats. Brain Res. 551, 145–149 (1991).
Banks, W. A., Moinuddin, A. & Morley, J. E. Regional transport of TNF-α across the blood–brain barrier in young ICR and young and aged SAMP8 mice. Neurobiol. Aging 22, 671–676 (2001).
Banks, W. A. & Kastin, A. J. Aging and the blood-brain barrier: changes in the carrier-mediated transport of peptides in rats. Neurosci. Lett. 61, 171–175 (1985).
Toornvliet, R. et al. Effect of age on functional P-glycoprotein in the blood–brain barrier measured by use of (R)-[11C]verapamil and positron emission tomography. Clin. Pharmacol. Ther. 79, 540–548 (2006).
Pan, Y. & Nicolazzo, J. A. Impact of aging, Alzheimer’s disease and Parkinson’s disease on the blood–brain barrier transport of therapeutics. Adv. Drug Deliv. Rev. 135, 62–74 (2018).
Palmer, A. L. & Ousman, S. S. Astrocytes and aging. Front. Aging Neurosci. 10, 337 (2018).
Li, Y. et al. Aging neurovascular unit and potential role of DNA damage and repair in combating vascular and neurodegenerative disorders. Front. Neurosci. 13, 778 (2019).
Boisvert, M. M., Erikson, G. A., Shokhirev, M. N. & Allen, N. J. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22, 269–285 (2018).
Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. USA 115, E1896–E1905 (2018).
Miller, W. J. et al. Mechanically induced reactive gliosis causes ATP-mediated alterations in astrocyte stiffness. J. Neurotrauma 26, 789–797 (2009).
Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019).
Scioli, M. G., Bielli, A., Arcuri, G., Ferlosio, A. & Orlandi, A. Ageing and microvasculature. Vasc. Cell 6, 19 (2014).
Hawkes, C. A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).
Hawkes, C. A. et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell 12, 224–236 (2013).
Syková, E., Mazel, T. & Šimonová, Z. Diffusion constraints and neuron–glia interaction during aging. Exp. Gerontol. 33, 837–851 (1998).
Keable, A. et al. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 1862, 1037–1046 (2016).
Raffetto, J. D. & Khalil, R. A. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem. Pharm. 75, 346–359 (2008).
Ceafalan, L. C. et al. Age-related ultrastructural changes of the basement membrane in the mouse blood–brain barrier. J. Cell. Mol. Med. 23, 819–827 (2019).
Zobel, K., Hansen, U. & Galla, H.-J. Blood-brain barrier properties in vitro depend on composition and assembly of endogenous extracellular matrices. Cell Tissue Res. 365, 233–245 (2016).
Paone, L. S., Benmassaoud, M. M., Curran, A., Vega, S. L. & Galie, P. A. A 3D-printed blood-brain barrier model with tunable topology and cell–matrix interactions. Biofabrication 16, 015005 (2024).
Sierra, C. Hypertension and the risk of dementia. Front Cardiovasc Med. 7, 5 (2020).
Nortley, R. et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365, eaav9518 (2019).
Budday, S., Ovaert, T. C., Holzapfel, G. A., Steinmann, P. & Kuhl, E. Fifty shades of brain: a review on the mechanical testing and modeling of brain tissue. Arch. Comput. Methods Eng. 27, 1187–1230 (2020).
Braun, J. et al. High-resolution mechanical imaging of the human brain by three-dimensional multifrequency magnetic resonance elastography at 7T. NeuroImage 90, 308–314 (2014).
Liao, J., Yang, H., Yu, J., Liang, X. & Chen, Z. Progress in the application of ultrasound elastography for brain diseases. J. Ultrasound Med. 39, 2093–2104 (2020).
Albakr, A. et al. Ultrasound elastography in neurosurgery: current applications and future perspectives. World Neurosurg. 170, 195–205.e1 (2023).
Bayly, P. V. et al. MR imaging of human brain mechanics in vivo: new measurements to facilitate the development of computational models of brain injury. Ann. Biomed. Eng. 49, 2677–2692 (2021).
Loomis, A. L. & Chakko, M. N. Doppler Trans-cranial Assessment, Protocols, and Interpretation (StatPearls Publishing LLC., Treasure Island, FL, 2024).
van Dinther, M. et al. Assessment of microvascular rarefaction in human brain disorders using physiological magnetic resonance imaging. J. Cereb. Blood Flow Metab. 42, 718–737 (2022).
Walsh, C. L. et al. Imaging intact human organs with local resolution of cellular structures using hierarchical phase-contrast tomography. Nat. Methods 18, 1532–1541 (2021).
Chaulagain, B. et al. Experimental models of in vitro blood–brain barrier for CNS drug delivery: an evolutionary perspective. Int. J. Mol. Sci. 24, 2710 (2023).
O’Brown, N. M., Pfau, S. J. & Gu, C. Bridging barriers: a comparative look at the blood–brain barrier across organisms. Genes Dev. 32, 466–478 (2018).
Thomsen, M. S. et al. The blood–brain barrier studied in vitro across species. PLoS ONE 16, e0236770 (2021).
Mármol, I., Abizanda-Campo, S., Ayuso, J. M., Ochoa, I. & Oliván, S. Towards novel biomimetic in vitro models of the blood–brain barrier for drug permeability evaluation. Bioengineering 10, 572 (2023).
Cramer, S. W. et al. Through the looking glass: a review of cranial window technology for optical access to the brain. J. Neurosci. Methods 354, 109100 (2021).
Fan, J. L. et al. High-speed volumetric two-photon fluorescence imaging of neurovascular dynamics. Nat. Commun. 11, 6020 (2020).
Giblin, J. T. et al. Measuring capillary flow dynamics using interlaced two-photon volumetric scanning. J. Cereb. Blood Flow. Metab. 43, 595–609 (2023).
Ge, G. R. et al. Mouse brain elastography changes with sleep/wake cycles, aging, and Alzheimer’s disease. NeuroImage 295, 120662 (2024).
Vardakis, J. C. et al. Fluid–structure interaction for highly complex, statistically defined, biological media: homogenisation and a 3D multi-compartmental poroelastic model for brain biomechanics. J. Fluids Struct. 91, 102641 (2019).
Kaisar, M. A. et al. New experimental models of the blood–brain barrier for CNS drug discovery. Expert Opin. Drug Discov. 12, 89–103 (2017).
Delsing, L. et al. Models of the blood–brain barrier using iPSC-derived cells. Mol. Cell. Neurosci. 107, 103533 (2020).
Wolburg, H., Noell, S., Wolburg-Buchholz, K., Mack, A. & Fallier-Becker, P. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood–brain barrier. Neuroscientist 15, 180–193 (2009).
Hajal, C. et al. Engineered human blood–brain barrier microfluidic model for vascular permeability analyses. Nat. Protoc. 17, 95–128 (2022).
Antonacci, G. et al. Quantification of plaque stiffness by Brillouin microscopy in experimental thin cap fibroatheroma. J. R. Soc. Interface 12, 20150843 (2015).
Nerger, B. A., Siedlik, M. J. & Nelson, C. M. Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis. Cell. Mol. Life Sci. 74, 1819–1834 (2017).
Bustamante, C. J., Chemla, Y. R., Liu, S. & Wang, M. D. Optical tweezers in single-molecule biophysics. Nat. Rev. Methods Prim. 1, 25 (2021).
Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).
Charrier, E. E. et al. The desmin network is a determinant of the cytoplasmic stiffness of myoblasts. Biol. Cell 110, 77–90 (2018).
Keating, C. E. & Cullen, D. K. Mechanosensation in traumatic brain injury. Neurobiol. Dis. 148, 105210 (2021).
Baldwin, S. A., Fugaccia, I., Brown, D. R., Brown, L. V. & Scheff, S. W. Blood–brain barrier breach following cortical contusion in the rat. J. Neurosurg. 85, 476–481 (1996).
Başkaya, M. K., Muralikrishna Rao, A., Doğan, A., Donaldson, D. & Dempsey, R. J. The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci. Lett. 226, 33–36 (1997).
Svedung Wettervik, T., Fahlström, M., Enblad, P. & Lewén, A. Cerebral pressure autoregulation in brain injury and disorders–a review on monitoring, management, and future directions. World Neurosurg. 158, 118–131 (2022).
Ahmed, S. M., Rzigalinski, B. A., Willoughby, K. A., Sitterding, H. A. & Ellis, E. F. Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons. J. Neurochem. 74, 1951–1960 (2000).
Neary, J. T., Kang, Y., Willoughby, K. A. & Ellis, E. F. Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J. Neurosci. 23, 2348–2356 (2003).
Floyd, C. L., Gorin, F. A. & Lyeth, B. G. Mechanical strain injury increases intracellular sodium and reverses Na+/Ca2+ exchange in cortical astrocytes. Glia 51, 35–46 (2005).
Maneshi, M. M., Sachs, F. & Hua, S. Z. Heterogeneous cytoskeletal force distribution delineates the onset Ca2+ influx under fluid shear stress in astrocytes. Front. Cell. Neurosci. 12, 69 (2018).
Maxwell, W. L., Irvine, A., Adams, J. H., Graham, D. I. & Gennarelli, T. A. Response of cerebral microvasculature to brain injury. J. Pathol. 155, 327–335 (1988).
Boulet, T., Kelso, M. L. & Othman, S. F. Long-term in vivo imaging of viscoelastic properties of the mouse brain after controlled cortical impact. J. Neurotrauma 30, 1512–1520 (2013).
Carrano, A. et al. Amyloid beta induces oxidative stress-mediated blood–brain barrier changes in capillary amyloid angiopathy. Antioxid. Redox Signal. 15, 1167–1178 (2011).
Sin, M.-K., Zamrini, E., Ahmed, A., Nho, K. & Hajjar, I. Anti-amyloid therapy, AD, and ARIA: untangling the role of CAA. J. Clin. Med. 12, 6792 (2023).
Velasco-Estevez, M. et al. Infection augments expression of mechanosensing Piezo1 channels in amyloid plaque-reactive astrocytes. Front. Aging Neurosci. 10, 332 (2018).
Murphy, M. C. et al. Decreased brain stiffness in Alzheimer’s disease determined by magnetic resonance elastography. J. Magn. Reson. Imaging 34, 494–498 (2011).
Hiscox, L. V. et al. Mechanical property alterations across the cerebral cortex due to Alzheimer’s disease. Brain Commun. 2, fcz049 (2019).
Munder, T. et al. MR elastography detection of early viscoelastic response of the murine hippocampus to amyloid β accumulation and neuronal cell loss due to Alzheimer’s disease. J. Magn. Reson. Imaging 47, 105–114 (2018).
Merlini, M., Meyer, E. P., Ulmann-Schuler, A. & Nitsch, R. M. Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol. 122, 293–311 (2011).
Taylor, X. et al. A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy. J. Neuroinflamm. 17, 223 (2020).
Spampinato, S. F., Merlo, S., Sano, Y., Kanda, T. & Sortino, M. A. Astrocytes contribute to Aβ-induced blood–brain barrier damage through activation of endothelial MMP9. J. Neurochem. 142, 464–477 (2017).
Ventura-Antunes, L. et al. Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase. Alzheimer's Dement. 21, 70254 (2025).
Wilhelmus, M. M. M., Bol, J. G. J. M., van Duinen, S. G. & Drukarch, B. Extracellular matrix modulator lysyl oxidase colocalizes with amyloid-beta pathology in Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis—Dutch type. Exp. Gerontol. 48, 109–114 (2013).
de Jager, M. et al. Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy. Neurobiol. Aging 34, 1159–1169 (2013).
Bonneh-Barkay, D. & Wiley, C. A. Brain extracellular matrix in neurodegeneration. Brain Pathol. 19, 573–585 (2009).
Held, F. et al. Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Clin. Sci. 131, 1001–1013 (2017).
Lepelletier, F. X., Mann, D. M. A., Robinson, A. C., Pinteaux, E. & Boutin, H. Early changes in extracellular matrix in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 43, 167–182 (2017).
Ochi, N. et al. Silent cerebral microbleeds associated with arterial stiffness in an apparently healthy subject. Hypertens. Res. 32, 255–260 (2009).
Buée, L. et al. Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathol. 87, 469–480 (1994).
Bell, M. A. & Ball, M. J. Morphometric comparison of hippocampal microvasculature in ageing and demented people: diameters and densities. Acta Neuropathol. 53, 299–318 (1981).
Cho, D. H., Aguayo, S. & Cartagena-Rivera, A. X. Atomic force microscopy-mediated mechanobiological profiling of complex human tissues. Biomaterials 303, 122389 (2023).
Wirtz, D. Particle-Tracking Microrheology of Living Cells: Principles and Applications. Annu. Rev. Biophys. 38, 301–326 (2009).
Català-Castro, F., Schäffer, E. & Krieg, M. Exploring cell and tissue mechanics with optical tweezers. J. Cell Sci. 135, jcs259355 (2022).
Gaire S, R. F. Jr, Pegg, I. & Sarkar, A. Magnetic tweezers: development and use in single-molecule research. BioTechniques 72, 65–72 (2022).
Kabakova, I. et al. Brillouin microscopy. Nat. Rev. Methods Prim. 4, 8 (2024).
Scarcelli, G. et al. Noncontact three-dimensional mapping of intracellular hydromechanical properties by Brillouin microscopy. Nat. Methods 12, 1132–1134 (2015).
Lekka, M., Gnanachandran, K., Kubiak, A., Zieliński, T. & Zemła, J. Traction force microscopy—measuring the forces exerted by cells. Micron 150, 103138 (2021).
Liu, L., He, F., Yu, Y. & Wang, Y. Application of FRET biosensors in mechanobiology and mechanopharmacological screening. Front. Bioeng. Biotechnol. 8, 595497 (2022).
Acknowledgements
We are grateful for financial support from the BBSRC (BB/V001418/1), the Cancer Research UK Multidisciplinary Award (C57744/A22057), and EPSRC (EP/W009889/1) to E.M.
Author information
Authors and Affiliations
Contributions
S.K. conceived and wrote the manuscript, prepared the figures, and edited the manuscript. V.J. assisted with manuscript revisions and contributed to sections of the article and figures. S.W. and R.K. contributed sections of the article and assisted with the refinement and editing of the paper. E.M. conceived the manuscript, contributed sections, reviewed and edited it, supervised the work, and acquired funding. All authors read and approved the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare the following competing interests: Emad Moeendarbary is the founder of BioRecode Ltd. RDK is a co-founder of AIM Biotech, a company that markets microfluidic technologies and receives research support from Amgen, AbbVie, Boehringer-Ingelheim, Daiichi-Sankyo, Novartis, Roche, Takeda, Eisai, EMD Serono and Visterra. None of these activities is related to the content of this article. The other authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Ethan Lippmann, who co-reviewed with Daniel Chavarria, Luca Cucullo and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Konig, S., Jayarajan, V., Wray, S. et al. Mechanobiology of the blood-brain barrier during development, disease and ageing. Nat Commun 16, 7233 (2025). https://doi.org/10.1038/s41467-025-61888-7
Received:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41467-025-61888-7
