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Rationale

The extracellular matrix protein, fibronectin (FN), is focally deposited in regions of atherosclerosis where it contributes to inflammatory signaling.

Objective

To elucidate the mechanism by which FN deposition is regulated by local shear stress patterns, its dependence on PECAM-1 mechanotransduction, and the role this pathway plays in sustaining an atheroprone/pro-inflammatory phenotype.

Methods and Results

Human endothelial cells were exposed in vitro to atheroprone or atheroprotective shear stress patterns derived from human carotid arteries. Onset of atheroprotective flow induced a transient increase in FN deposition, whereas atheroprone flow caused a steady increase in FN expression and integrin activation over time, leading to a significant and sustained increase in FN deposition relative to atheroprotective conditions. Comparing FN staining in ApoE−/− and ApoE−/−PECAM−/− mice showed that PECAM-1 was essential for FN accumulation in atheroprone regions of the aortic arch. In vitro, siRNA against PECAM-1 blocked the induction of FN and the activation of NF-κB by atheroprone flow, which was rescued by the addition of exogenous FN. Additionally, blocking NF-κB activation attenuated the flow-induced FN expression. siRNA against FN significantly reduced NF-κB activity, which was rescued by the addition of exogenous FN.

Conclusions

These results indicate that FN gene expression and assembly into matrix fibrils is induced by atheroprone fluid shear stress. This effect is mediated at least in part by the transcription factor NF-κB. Additionally, because FN promotes activation of NF-κB, atheroprone shear stress creates a positive feedback to maintain inflammation.

Objective

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis.

Methods and Results

We crossed C57BL/6 Pecam1−/− mice with apolipoprotein E–deficient (Apoe−/−) mice. On a Western diet, Pecam1−/−Apoe−/− mice showed reduced atherosclerotic lesion size compared to Apoe−/− mice. Striking differences were observed in the lesser curvature of the aortic arch, an area of disturbed flow, but not in the descending thoracic or abdominal aorta. Vascular cell adhesion molecule-1 (VCAM-1) expression, macrophage infiltration, and endothelial nuclear NF-κB were all reduced in Pecam1−/−Apoe−/− mice. Bone marrow transplantation suggested that endothelial PECAM-1 is the main determinant of atherosclerosis in the aortic arch, but that hematopoietic PECAM-1 promotes lesions in the abdominal aorta. In vitro data show that siRNA-based knockdown of PECAM-1 attenuates endothelial NF-κB activity and VCAM-1 expression under conditions of atheroprone flow.

Conclusion

These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-κB–mediated gene expression.

Complex hemodynamics play a role in the localization and development of atherosclerosis. Endothelial cells (ECs) lining blood vessel walls are directly influenced by various hemodynamic forces: simultaneous wall shear stress (WSS), normal stress, and circumferential stress/strain (CS) due to pulsatile flow, pressure, and diameter changes. ECs sense and transduce these forces into biomolecular responses that may affect intercellular junctions. In this study, a hemodynamic simulator was used to investigate the combined effects of WSS and CS on EC junctions with emphasis on the stress phase angle (SPA), the temporal phase difference between WSS and CS. Regions of the circulation with highly negative SPA, such as the coronary arteries and carotid bifurcation, are more susceptible to the development of atherosclerosis. At 5 h, expression of the tight junction protein zonula occludens-1 was significantly higher for the atheroprotective SPA = 0° compared to the atherogenic SPA = −180° while the apoptosis rate was significantly higher for SPA = −180° than SPA = 0°. This decrease in tight junction protein and increase in apoptosis and associated leaky junctions suggest a decreased junctional stability and a higher paracellular permeability for atherogenic macromolecules for the atherogenic SPA = −180° compared to SPA = 0°.

The present review presents basic concepts of blood rheology related to vascular diseases. Blood flow in large arteries is dominated by inertial forces exhibited at high flow velocities, while viscous forces (i.e., blood rheology) play an almost negligible role. When high flow velocity is compromised by sudden deceleration as at a bifurcation, endothelial cell dysfunction can occur along the outer wall of the bifurcation, initiating inflammatory gene expression and, through mechanotransduction, the cascade of events associated with atherosclerosis. In sharp contrast, the flow of blood in microvessels is dominated by viscous shear forces since the inertial forces are negligible due to low flow velocities. Shear stress is a critical parameter in microvascular flow, and a force-balance approach is proposed for determining microvascular shear stress, accounting for the low Reynolds numbers and the dominance of viscous forces over inertial forces. Accordingly, when the attractive forces between erythrocytes (represented by the yield stress of blood) are greater than the shear force produced by microvascular flow, tissue perfusion itself cannot be sustained, leading to capillary loss. The yield stress parameter is presented as a diagnostic candidate for future clinical research, specifically, as a fluid dynamic biomarker for microvascular disorders. The relation between the yield stress and diastolic blood viscosity (DBV) is described using the Casson model for viscosity, from which one may be able determine thresholds of DBV where the risk of microvascular disorders is high.

Background

Dystrophin has a key role in striated muscles mechanotransduction of physical forces. Although cytoskeletal elements play a major role in the mechanotransduction of pressure and flow in vascular cells, the role of dystrophin in vascular functions has not yet been investigated. Thus we studied endothelial and muscular responses of arteries isolated from mice lacking dystrophin (mdx).

Methods and results

Carotid and mesenteric resistance arteries (120μm diameter) were isolated and mounted in vitro in an arteriograph to control intraluminal pressure and flow. Blood pressure was not affected by the absence of dystrophin. Pressure (myogenic)-, phenylephrine- and KCl-induced tone were unchanged. Flow (shear stress) -induced dilation in arteries isolated from mdx mice was decreased by 50 to 60%, whereas dilation to acetylcholine or sodium nitroprusside were unaffected. L-NAME-sensitive flow-dilation was also decreased in arteries from mdx mice. Thus the absence of dystrophin was associated to a defect in signal transduction of shear stress. Dystrophin was present in vascular endothelial and smooth muscle cells, as shown by immunolocalization and localized at the level of the plasma membrane, as seen by confocal microscopy of perfused isolated arteries.

Discussion

This is the first functional study of arteries lacking the gene for dystrophin. Vascular reactivity was normal with the exception of flow-induced dilation. Thus dystrophin could play a specific role in shear stress-mechanotransduction in arterial endothelial cells. Organs damages in diseases such as Duchenne’s dystrophy might be aggravated by such a defectuous arterial response to flow.

Short abstract

Dystrophin plays an active role in the transduction of mechanical forces in striated muscle. We showed that the absence of dystrophin altered specifically the mechanotransduction of shear stress due to flow by the endothelium of arteries isolated from mice lacking the gene for dystrophin (mdx), whereas other forms of vascular tone, dilators or constrictors, were unaffected.

Thus dystrophin plays a specific role in shear stress-mechanotransduction in arterial endothelial cells. Finally, organs damages in diseases such as Duchenne’s dystrophy might be aggravated by defectuous arterial responses to changes in blood flow.

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

Fluid shear stress is the mechanical force generated by the blood flow which is applied over the apical surface of endothelial cells in situ. The findings of a recent study suggest that stress fibers and its associated focal adhesions play roles in mechano-signal transduction mechanism. Stress fibers are present along the apical and the basal portion of the endothelial cells. Endothelial cells respond to fluid shear stress and change their morphological characteristics in both their cell shape and cytoskeletal organization. Atherosclerosis is a common disease of the arteries and it occurs in areas around the branching site of blood vessels where the cells are exposed to low fluid shear stress. The organization of stress fibers and focal adhesions are strongly influenced by shear stress, and therefore the generation of atherosclerotic lesions seem to be associated with the cytoskeletal components of endothelial cells. This review describes the possible role of the cytoskeleton as a mechano-transducer in endothelial cells in situ.

OBJECTIVE

Vascular remodeling is a physiological process that occurs in response to long-term changes in hemodynamic conditions, but may also contribute to the pathophysiology of intima-media thickening (IMT) and vascular disease. Shear stress detection by the endothelium is thought to be an important determinant of vascular remodeling. Previous work showed that Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensory complex that mediates endothelial cell (EC) responses to shear stress.

METHODS AND RESULTS

We tested the hypothesis that PECAM-1 contributes to vascular remodeling by analyzing the response to partial carotid artery ligation in PECAM-1 knockout mice and wild-type littermates. PECAM-1 deficiency resulted in impaired vascular remodeling and significantly reduced IMT in areas of low flow. Inward remodeling was associated with PECAM-1-dependent NFκB activation, surface adhesion molecule expression and leukocyte infiltration as well as Akt activation and vascular cell proliferation.

CONCLUSIONS

PECAM-1 plays a crucial role in the activation of the NFκB and Akt pathways and inflammatory cell accumulation during vascular remodeling and IMT. Elucidation of some of the signals that drive vascular remodeling represent pharmacologically tractable targets for the treatment of restenosis after balloon angioplasty or stent placement.

Vascular endothelial cells lining the blood vessels form the interface between the bloodstream and the vessel wall and as such they are continuously subjected to shear and cyclic stress from the flowing blood in the lumen. Additional mechanical stimuli are also imposed on these cells in the form of substrate stiffness transmitted from the extracellular matrix components in the basement membrane, and additional mechanical loads imposed on to lung endothelium as result of respiration or mechanical ventilation in clinical settings. Focal adhesions (FAs) are complex structures assembled at the abluminal endothelial plasma membrane which connect the extracellular filamentous meshwork to the intracellular cytoskeleton and hence constitute the ideal checkpoint capable of controlling or mediating transduction of bidirectional mechanical signals. In this review we focus on focal adhesion kinase (FAK), a component of FAs, which has been studied for a number of years with regards to its involvement in mechanotransduction. We analyzed the recent advances in the understanding of the role of FAK in the signaling cascade(s) initiated by various mechanical stimuli with particular emphasis on potential implications on endothelial cell functions.

Understanding how vascular wall endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) sense and transduce the stimuli of hemodynamic forces (shear stress, cyclic strain, and hydrostatic pressure) into intracellular biochemical signals is critical to prevent vascular disease development and progression. ECs lining the vessel lumen directly sense alterations in blood flow shear stress and then communicate with medial SMCs and adventitial FBs to regulate vessel function and disease. Shear stress mechanotransduction in ECs has been extensively studied and reviewed. In the case of endothelial damage, blood flow shear stress may directly act on the superficial layer of SMCs and transmural interstitial flow may be elevated on medial SMCs and adventitial FBs. Therefore, it is also important to investigate direct shear effects on vascular SMCs as well as FBs. The work published in the last two decades has shown that shear stress and interstitial flow have significant influences on vascular SMCs and FBs. This review summarizes work that considered direct shear effects on SMCs and FBs and provides the first comprehensive overview of the underlying mechanisms that modulate SMC secretion, alignment, contraction, proliferation, apoptosis, differentiation, and migration in response to 2-dimensional (2D) laminar, pulsatile, and oscillating flow shear stresses and 3D interstitial flow. A mechanistic model of flow sensing by SMCs is also provided to elucidate possible mechanotransduction pathways through surface glycocalyx, integrins, membrane receptors, ion channels, and primary cilia. Understanding flow-mediated mechanotransduction in SMCs and FBs and the interplay with ECs should be helpful in exploring strategies to prevent flow-initiated atherosclerosis and neointima formation and has implications in vascular tissue engineering.

Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS) in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known. Here we show that abnormal flow-dependent remodeling in eNOS knockout mice (eNOS (−/−)) is associated with activation of the platelet derived growth factor (PDGF) signaling pathway leading to the induction of the inhibitor of apoptosis, survivin. Interfering with PDGF signaling or survivin function corrects the abnormal remodeling seen in eNOS (−/−) mice. Moreover, nitric oxide (NO) negatively regulates PDGF driven survivin expression and cellular proliferation in cultured vascular smooth muscle cells. Collectively, our data suggests that eNOS negatively regulates the PDGF-survivin axis to maintain proportional flow-dependent luminal remodeling and vascular quiescence.

Recirculation of fluid and cells through lymphatic vessels plays a key role in normal tissue homeostasis, inflammatory diseases, and cancer. Despite recent advances in understanding lymphatic function (Alitalo, K., T. Tammela, and T.V. Petrova. 2005. Nature. 438:946–953), the cellular features responsible for entry of fluid and cells into lymphatics are incompletely understood. We report the presence of novel junctions between endothelial cells of initial lymphatics at likely sites of fluid entry. Overlapping flaps at borders of oak leaf–shaped endothelial cells of initial lymphatics lacked junctions at the tip but were anchored on the sides by discontinuous button-like junctions (buttons) that differed from conventional, continuous, zipper-like junctions (zippers) in collecting lymphatics and blood vessels. However, both buttons and zippers were composed of vascular endothelial cadherin (VE-cadherin) and tight junction–associated proteins, including occludin, claudin-5, zonula occludens–1, junctional adhesion molecule–A, and endothelial cell–selective adhesion molecule. In C57BL/6 mice, VE-cadherin was required for maintenance of junctional integrity, but platelet/endothelial cell adhesion molecule–1 was not. Growing tips of lymphatic sprouts had zippers, not buttons, suggesting that buttons are specialized junctions rather than immature ones. Our findings suggest that fluid enters throughout initial lymphatics via openings between buttons, which open and close without disrupting junctional integrity, but most leukocytes enter the proximal half of initial lymphatics.

Abstract

The endothelium lining the inner surface of blood vessels of the cardiovascular system is constantly exposed to hemodynamic shear stress. The interaction between endothelial cells and hemodynamic shear stress has critical implications for atherosclerosis. Regions of arterial narrowing, curvatures, and bifurcations are especially susceptible to atherosclerotic lesion formation. In such areas, endothelial cells experience low, or oscillatory, shear stress. Corresponding changes in endothelial cell structure and function make them susceptible to the initiation and development of atherosclerosis. In contrast, blood flow with high laminar shear stress activates signal transductions as well as gene and protein expressions that play important roles in vascular homeostasis. In response to laminar shear stress, the release of vasoactive substances such as nitric oxide and prostacyclin decreases permeability to plasma lipoproteins as well as the adhesion of leukocytes, and inhibits smooth muscle cell proliferation and migration. In summary, different flow patterns directly determine endothelial cell morphology, metabolism, and inflammatory phenotype through signal transduction and gene and protein expression. Thus, high laminar shear stress plays a key role in the prevention of atherosclerosis through its regulation of vascular tone and long-term maintenance of the integrity and function of endothelial cells. Antioxid. Redox Signal. 11, 1669–1682.

It has become evident that mechanical forces play a key role in cancer metastasis, a complex series of steps that is responsible for the majority of cancer-related deaths. One such force is fluid shear stress, exerted on circulating tumor cells by blood flow in the vascular microenvironment, and also on tumor cells exposed to slow interstitial flows in the tumor microenvironment. Computational and experimental models have the potential to elucidate metastatic behavior of cells exposed to such forces. Here, we review the fluid-generated forces that tumor cells are exposed to in the vascular and tumor microenvironments, and discuss recent computational and experimental models that have revealed mechanotransduction phenomena that may play a role in the metastatic process.

Mechanotransduction, the process by which cells convert external mechanical stimuli such as fluid shear stress (FSS) into biochemical changes, plays a critical role in maintenance of the skeleton. We have proposed that mechanical stimulation by FSS across the surfaces of bone cells results in formation of unique signaling complexes called mechanosomes that are launched from sites of adhesion with the extracellular matrix and with other bone cells [1]. Deformation of adhesion complexes at the cell membrane ultimately results in alteration of target gene expression. Recently, we reported that focal adhesion kinase (FAK) functions as a part of a mechanosome complex that is required for FSS-induced mechanotransduction in bone cells. This study extends this work to examine the role of a second member of the FAK family of non-receptor protein tyrosine kinases, proline-rich tyrosine kinase 2 (Pyk2), and determine its role during osteoblast mechanotransduction. We use osteoblasts harvested from mice as our model system in this study and compared the contributions of Pyk2 and FAK during FSS induced mechanotransduction in osteoblasts. We exposed Pyk2+/+ and Pyk2−/− primary calvarial osteoblasts to short period of oscillatory fluid flow and analyzed downstream activation of ERK1/2, and expression of c-fos, cyclooxygenase-2 and osteopontin. Unlike FAK, Pyk2 was not required for fluid flow-induced mechanotransduction as there was no significant difference in the response of Pyk2+/+ and Pyk2−/− osteoblasts to short periods of fluid flow (FF). In contrast, and as predicted, FAK−/− osteoblasts were unable to respond to FF. These data indicate that FAK and Pyk2 have distinct, non-redundant functions in launching mechanical signals during osteoblast mechanotransduction. Additionally, we compared two methods of generating FF in both cell types, oscillatory pump method and another orbital platform method. We determined that both methods of generating FF induced similar responses in both primary calvarial osteoblasts and immortalized calvarial osteoblasts.

Caveolae in endothelial cells have been implicated as plasma membrane microdomains that sense or transduce hemodynamic changes into biochemical signals that regulate vascular function. Therefore we compared long- and short-term flow-mediated mechanotransduction in vessels from WT mice, caveolin-1 knockout (Cav-1 KO) mice, and Cav-1 KO mice reconstituted with a transgene expressing Cav-1 specifically in endothelial cells (Cav-1 RC mice). Arterial remodeling during chronic changes in flow and shear stress were initially examined in these mice. Ligation of the left external carotid for 14 days to lower blood flow in the common carotid artery reduced the lumen diameter of carotid arteries from WT and Cav-1 RC mice. In Cav-1 KO mice, the decrease in blood flow did not reduce the lumen diameter but paradoxically increased wall thickness and cellular proliferation. In addition, in isolated pressurized carotid arteries, flow-mediated dilation was markedly reduced in Cav-1 KO arteries compared with those of WT mice. This impairment in response to flow was rescued by reconstituting Cav-1 into the endothelium. In conclusion, these results showed that endothelial Cav-1 and caveolae are necessary for both rapid and long-term mechanotransduction in intact blood vessels.

The endothelial glycocalyx layer is a ~2 µm thick glycosaminoglycan rich pericellular matrix expressed on the luminal surface of vascular endothelial cells, which has implications in vessel mechanics and mechanotransduction. Despite its role in vascular physiology, no direct measurement has of yet been made of vessel glycocalyx material properties. Vaterite microviscometry is a laser tweezers based microrheological method, which has been previously utilized to measure the viscosity of linear and complex fluids under flow. This form of microrheology has until now relied on complete recollection of the forward scattered light. Here we present a novel method to extend vaterite microviscometry to relatively thick samples. We validate our method and its assumptions and measure the apparent viscosity as a function of distance from the vascular endothelium. We observe a differential response in conditions designed to preserve the EGL in comparison to those designed to collapse it.

The integrity of the endothelial monolayer is essential to blood vessel homeostasis and active regulation of endothelial permeability. The FGF system plays important roles in a wide variety of physiologic and pathologic conditions; however, its role in the adult vasculature has not been defined. To assess the role of the FGF system in the adult endothelial monolayer, we disrupted FGF signaling in bovine aortic endothelial cells and human saphenous vein endothelial cells in vitro and in adult mouse and rat endothelial cells in vivo using soluble FGF traps or a dominant inhibitor of all FGF receptors. The inhibition of FGF signaling using these approaches resulted in dissociation of the VE-cadherin/p120-catenin complex and disassembly of adherens and tight junctions, which progressed to loss of endothelial cells, severe impairment of the endothelial barrier function, and finally, disintegration of the vasculature. Thus, FGF signaling plays a key role in the maintenance of vascular integrity.

Mechanosensing followed by mechanoresponses by cells is well established, but the mechanisms by which mechanical force is converted into biochemical events are poorly understood. Vascular endothelial cells (ECs) exhibit flow- and stretch-dependent responses and are widely used as a model for studying mechanotransduction in mammalian cells. Platelet EC adhesion molecule 1 (PECAM-1) is tyrosine phosphorylated when ECs are exposed to flow or when PECAM-1 is directly pulled, suggesting that it is a mechanochemical converter. We show that PECAM-1 phosphorylation occurs when detergent-extracted EC monolayers are stretched, indicating that this phosphorylation is mechanically triggered and does not require the intact plasma membrane and soluble cytoplasmic components. Using kinase inhibitors and small interfering RNAs, we identify Fyn as the PECAM-1 kinase associated with the model. We further show that stretch- and flow-induced PECAM-1 phosphorylation in intact ECs is abolished when Fyn expression is down-regulated. We suggest that PECAM-1 and Fyn are essential components of a PECAM-1–based mechanosensory complex in ECs.

Rationale

Hemodymic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensorycomplex that mediates endothelial cell (EC) responses to shearstress.

Objective

We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling.

Methods and Results

PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, due to deficits in shear stress-induced signaling, including activation of the NF-κB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and MCP-1, two stretch-induced regulators of arteriogenesis, both in vitro and in vivo.

Conclusions

Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter.

Background

The fibroblast growth factor (FGF) system plays a critical role in the maintenance of vascular integrity via enhancing the stability of VE-cadherin at adherens junctions. However, the precise molecular mechanism is not well understood. In the present study, we aimed to investigate the detailed mechanism of FGF regulation of VE-cadherin function that leads to endothelial junction stabilization.

Methods and Findings

In vitro studies demonstrated that the loss of FGF signaling disrupts the VE-cadherin-catenin complex at adherens junctions by increasing tyrosine phosphorylation levels of VE-cadherin. Among protein tyrosine phosphatases (PTPs) known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation. Increased endothelial permeability caused by FGF signaling inhibition was rescued by SHP2 overexpression, indicating the critical role of SHP2 in the maintenance of endothelial junction integrity.

Conclusions

These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability.

In blood vessels, endothelia are submitted to constant shear effects and are, under normal conditions, capable of responding to any variation in hemodynamic forces. Caveolae — 50- to 100-nm plasma membrane invaginations present at the surface of terminally differentiated cells and particularly enriched in ECs — are composed of a high sphingolipid and cholesterol content and the protein caveolin-1 (Cav-1). Previous studies have suggested that caveolae and endothelial Cav-1 may regulate the vascular response to altered shear stress. In this issue of the JCI, Yu et al. have examined the role of Cav-1/caveolae in the regulation of flow-induced alterations (i.e., mechanotransduction) in vessels from wild-type mice, Cav-1–deficient mice, and Cav-1–deficient mice re-expressing Cav-1 only in ECs. Their data suggest that caveolae/Cav-1 may act as sensors of altered shear stress and that they also organize the signaling response in stimulated ECs (see the related article beginning on page 1284).

Summary

Endothelial cells form cell-cell adhesive structures, called adherens and tight junctions, which maintain tissue integrity, but must be dynamic for leukocyte transmigration during the inflammatory response and cellular remodeling during angiogenesis. This review will focus on Vascular Endothelial (VE)-cadherin, an endothelial-specific cell-cell adhesion protein of the adherens junction complex. VE-cadherin plays a key role in endothelial barrier function and angiogenesis, and consequently VE-cadherin availability and function are tightly regulated. VE-cadherin also participates directly and indirectly in intracellular signaling pathways that control cell dynamics and cell cycle progression. Here we highlight recent work that has advanced our understanding of multiple regulatory and signaling mechanisms that converge on VE-cadherin and have consequences for endothelial barrier function and angiogenic remodeling.

A number of important changes take place in the maternal uterine vasculature during the first few weeks of pregnancy resulting in increased blood flow to the intervillous space. Vascular endothelial and smooth muscle cells are lost from the spiral arteries and are replaced by fetal trophoblast cells. Failure of the vessels to remodel sufficiently is a common feature of pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and pre-eclampsia. There is evidence to suggest that some vascular changes occur prior to trophoblast invasion, however, in the absence of trophoblasts remodelling of the spiral arteries is reduced. Until recently our knowledge of these events has been obtained from immunohistochemical studies which, although extremely useful, can give little insight into the mechanisms involved. With the development of more complex in vitro models a picture of events at a cellular and molecular level is beginning to emerge, although some caution is required in extrapolating to the in vivo situation. Trophoblasts synthesise and release a plethora of cytokines and growth factors including members of the tumour necrosis factor family. Studies suggest that these factors may be important in regulating the remodelling process by inducing both endothelial and vascular smooth muscle cell apoptosis. In addition, it is evident from studies in other vascular beds that the structure of the vessel is influenced by factors such as flow, changes in the composition of the extracellular matrix, the phenotype of the vascular cells and the local immune cell environment. It is the aim of this review to present our current knowledge of the mechanisms involved in spiral artery remodelling and explore other possible pathways and cellular interactions that may be involved, informed by studies in the cardiovascular field.

Summary

Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal is critical for our ability to hear and to maintain balance. Recent findings indicate that two members of the cadherin superfamily are components of the mechanotransduction machinery in sensory hair cells of the vertebrate inner ear. These studies show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) form several of the extracellular filaments that connect the stereocilia and kinocilium of a hair cell into a bundle. One of these filaments is the tip link that has been proposed to gate the mechanotransduction channel in hair cells. The extracellular domains of CDH23 and PCDH15 differ in their structure from classical cadherins and their cytoplasmic domains bind to distinct effectors, suggesting that evolutionary pressures have shaped the two cadherins for their function in mechanotransduction.