Endothelial Mechanosignaling: Does One Sensor Fit All?

Significance: Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Residing at the blood vessel interface, cells (endothelial cell, EC) are constantly exposed to vascular forces, including shear stress. Shear stress is the frictional force exerted by blood flow, and its patterns differ based on vessel geometry and type. These patterns range from uniform laminar flow to nonuniform disturbed flow. Although ECs sense and differentially respond to flow patterns unique to their microenvironment, the mechanisms underlying endothelial mechanosensing remain incompletely understood. Recent Advances: A large body of work suggests that ECs possess many mechanosensors that decorate their apical, junctional, and basal surfaces. These potential mechanosensors sense blood flow, translating physical force into biochemical signaling events. Critical Issues: Understanding the mechanisms by which proposed mechanosensors sense and respond to shear stress requires an integrative approach. It is also critical to understand the role of these mechanosensors not only during embryonic development but also in the different vascular beds in the adult. Possible cross talk and integration of mechanosensing via the various mechanosensors remain a challenge. Future Directions: Determination of the hierarchy of endothelial mechanosensors is critical for future work, as is determination of the extent to which mechanosensors work together to achieve force-dependent signaling. The role and primary sensors of shear stress during development also remain an open question. Finally, integrative approaches must be used to determine absolute mechanosensory function of potential mechanosensors. Antioxid. Redox Signal. 25, 373–388

S1P1 Bridges Mechanotransduction and Angiogenesis during Vascular Development

Mechanisms of stabilization of the vascular plexus and the role of mechanotransduction in this process are not well understood. In this issue of Developmental Cell, Jung et al. (2012) and Gaengel et al. (2012) describe the ligand-sensitive and mechanosensitive functions of an important vascular G protein-coupled receptor, S1P1

Hemodynamic forces in endothelial dysfunction and vascular aging

Aging is a key risk factor associated with the associated onset of cardiovascular disease. Notably, vascular aging and cardiovascular disease are both with endothelial dysfunction, or a marked decrease in production and bioavailability the vasodilator of nitric oxide (NO). As a result of decreased nitric oxide availability, aging vessels often exhibit endothelial cell senescence and increased oxidative stress. One of the most potent activators of NO production is fluid shear stress produced by blood flow. Interestingly, age-related decrease in NO production partially results from endothelial insensitivity to shear stress. While the endothelial cell response to fluid shear stress has been well characterized in recent years, the exact mechanisms of how the mechanical force of fluid shear stress is converted into intracellular biochemical signals are relatively unknown. Therefore, gaining a better knowledge of mechanosignaling events in endothelial cells may prove to be beneficial for developing potential therapies for cardiovascular diseases

Haemodynamics Regulate Fibronectin Assembly via PECAM

Fibronectin (FN) assembly and fibrillogenesis are critically important in both development and the adult organism, but their importance in vascular functions is not fully understood. Here we identify a novel pathway by which haemodynamic forces regulate FN assembly and fibrillogenesis during vascular remodelling. Induction of disturbed shear stress in vivo and in vitro resulted in complex FN fibril assembly that was dependent on the mechanosensor PECAM. Loss of PECAM also inhibited the cell-intrinsic ability to remodel FN. Gain- and loss-of-function experiments revealed that PECAM-dependent RhoA activation is required for FN assembly. Furthermore, PECAM−/− mice exhibited reduced levels of active β1 integrin that were responsible for reduced RhoA activation and downstream FN assembly. These data identify a new pathway by which endothelial mechanotransduction regulates FN assembly and flow-mediated vascular remodelling

Proteostasis and resilience in the mechanically-stressed vascular endothelium

Endothelial homeostasis is a central feature of vascular health. The vascular endothelium is under constant mechanical stress resulting from blood flow and, therefore, requires a high degree of resilience to adapt to stresses and resist development of disease. In this review, we discuss the molecular mechanisms by which the endothelium maintains proteostasis in response to haemodynamic forces by regulating three key areas: protein synthesis, recycling and degradation

Spatial signaling networks converge at the adaptor protein Shc

Endothelial cells, which are located at the interface between the blood and the vessel wall, respond dynamically to a variety of stimuli initiating signaling cascades that regulate cardiovascular development, physiology and pathology. These inputs include soluble factors that bind to their receptors, integrin-matrix interactions, cell-cell contacts and mechanical forces due to the flowing blood. While these stimuli can mediate unique downstream signals, it is well-accepted that signaling pathways are highly interwoven into complex signaling networks with several levels of cross-talk, integration and coordination. Recent studies suggest that several signaling networks coalesce at the adaptor protein Shc

Role of PECAM-1 in Arteriogenesis and Specification of Preexisting Collaterals

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

Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation

Atherosclerotic plaques develop in regions of the vasculature associated with chronic inflammation due to disturbed flow patterns. Endothelial phenotype modulation by flow requires the integration of numerous mechanotransduction pathways, but how this is achieved is not well understood. We show here that, in response to flow, the adaptor protein Shc is activated and associates with cell–cell and cell–matrix adhesions. Shc activation requires the tyrosine kinases vascular endothelial growth factor receptor 2 and Src. Shc activation and its vascular endothelial cadherin (VE-cadherin) association are matrix independent. In contrast, Shc binding to integrins requires VE-cadherin but occurs only on specific matrices. Silencing Shc results in reduction in both matrix-independent and matrix-dependent signals. Furthermore, Shc regulates flow-induced inflammatory signaling by activating nuclear factor κB–dependent signals that lead to atherogenesis. In vivo, Shc is activated in atherosclerosis-prone regions of arteries, and its activation correlates with areas of atherosclerosis. Our results support a model in which Shc orchestrates signals from cell–cell and cell–matrix adhesions to elicit flow-induced inflammatory signaling

Localized Tensional Forces on PECAM-1 Elicit a Global Mechanotransduction Response via the Integrin-RhoA Pathway

SummaryBackgroundMechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also of pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood.ResultsHere, we examine mechanochemical signaling in response to direct force application on PECAM-1. We demonstrate that localized tensional forces on PECAM-1 result in, surprisingly, global signaling responses. Specifically, force-dependent activation of phosphatidylinositol 3-kinase (PI3K) downstream of PECAM-1 promotes cell-wide activation of integrins and the small GTPase RhoA. These signaling events facilitate changes in cytoskeletal architecture, including growth of focal adhesions and adaptive cytoskeletal stiffening.ConclusionsTaken together, our work provides the first evidence of a global signaling event in response to a localized mechanical stress. In addition, these data provide a possible mechanism for the differential stiffness of vessels exposed to distinct hemodynamic force patterns in vivo

Endothelial Shc Regulates Arteriogenesis Through Dual Control of Arterial Specification and Inflammation via the Notch and Nuclear Factor- -Light-Chain-Enhancer of Activated B-Cell Pathways

Arteriogenesis, the shear stress-driven remodeling of collateral arteries, is critical in restoring blood flow to ischemic tissue following a vascular occlusion. Our previous work has shown that the adaptor protein Shc mediates endothelial responses to shear stress in vitro