Endothelial Mechanosignaling: Does One Sensor Fit All?

Abstract

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.

Role of hemodynamics in initiation/growth of intracranial aneurysms

“…Several ion channels including K + , Na + , Ca 2+ , TRPV (transient receptor potential cation channel) and Piezo 1/2 channels mediate the endothelial response to WSS. For instance, expressing K + channels into Xenopus laevis oocytes turns them sensitive to shear stress . The glycocalyx, a polycarbonate coat that covers the cell membrane, is also regulated by the WSS.…”

“…The glycocalyx, a polycarbonate coat that covers the cell membrane, is also regulated by the WSS. It has been shown that knocking‐down some core proteins of the glycocalyx leads to a failing of WSS‐induced eNOS and cytoskeleton remodelling . Caveolae are cholesterol‐ and sphingolipid‐rich microdomains that contain high levels of caveolin and cavin family proteins.…”

“…Caveolae are cup‐like invaginations containing many receptors and signalling molecules that may function as a signalling platform. The flattening of these structures by WSS or stretch would activate caveolin and induce responses through ERK, Rho GTPases, eNOS, Src family kinase and Akt activation . Primary cilia (PC) are microtubule‐based organelles that protrude at the apical side of most differentiated cells (ie, kidney, retina, liver epithelial cells, neuronal and vascular cells) and have numerous functions (chemosensing, mechanosensing, olfaction, photoreception).…”

“…Adherens junction proteins, principally VE‐cadherin, can also transmit extracellular force. In association with PECAM‐1 and VEGFR2/3, VE‐cadherin forms a mechanoresponsive complex, which stimulation leads to activation of the pro‐inflammatory NF‐κB pathway . A central core of WSS responsive elements is the cytoskeleton, whose remodelling is part of the early changes induced by flow.…”

Syndecan‐4, a model proteoglycan to study endothelial glycocalyx mechanosensing and signal transduction

“…One of the fastest endothelial responses to shear is activation of flow‐sensitive ion channels such as the inward rectifying K + channels and outward rectifying Cl ‐ channels, the transient receptor potential (TRP) family and mechanosensitive ion channels, the Piezo channels . Cell‐cell responsive complexes are formed by adhesion molecules such as the platelet endothelial cell adhesion molecule (PECAM‐1) and vascular endothelial (VE)‐cadherin in complex to other structural moieties . In cell‐to‐extracellular matrix interactions transmembrane proteins such as integrins have been of specific interest as biomechanical sensors, because of their connectivity to both the extracellular matrix and the cytoskeleton.…”