Figure 4.
The decentralized model of endothelial mechanotransduction by shear stress. The cytoskeleton has a central role in the transmission of tension changes throughout the cell. (A) Direct signaling can occur through deformation of the luminal surface, possibly via the glycocalyx. Examples include localized activation of potassium, sodium and calcium ion channels, phospholipase activity leading to calcium signaling, G-protein activation and caveolar signaling. (B) Mechanotransduction is also mediated via junctional signaling: that is, the transmission of forces to intercellular junction protein complexes via the cortical and/or filamentous cytoskeleton. VEGFR2 located at the luminal surface (see A) or near the junction (see B) can associate with VE-cadherin, β-catenin, and phosphatidylinositol 3 kinase to phosphorylate Akt and the primary transmembrane protein at this location, PECAM-1.59 (C) Cytoskeletal forces are also transmitted to adhesion sites. Transmembrane integrins bound to the extracellular matrix serve as a focus for deformation. This deformation results in autophosphorylation of FAK, which binds the SH2 domain of c-Src, a kinase family that phosphorylates paxillin and p130cas and leads to integrin-dependent activation of MAP kinases via Ras GTPase. A second parallel integrin-mediated pathway involves the activation of Shc, which binds Src family kinases through SH2 domains. Shc phosphorylation leads to Ras-MAP kinase activity.81 Ras releases the trans-acting NFκB from its cytosolic inhibitor, and thus enables its translocation to the nucleus where it binds to the promoters of multiple target genes. A third integrin-mediated pathway involves rhoA activation, which profoundly influences actin assembly and, therefore, transmission of mechanical stimuli. The multiple roles of small GTPases in mechanotransduction are reviewed in depth by Tzima.82 (D) Nuclear deformation is also likely to result in mechanically induced signaling, possibly via lamins in the nuclear membrane. Other possible direct effects include macromolecular conformation changes that are relevant to gene regulation. Of note, the locations are based on direct or indirect experimental evidence, are not mutually exclusive, and are probably interconnected. Permission obtained from Cambridge University Press © Davies PF and Helmke BP (2008) Endothelial Mechanotransduction. In Cellular Mechanotransduction: Diverse Perspectives from Molecules to Tissue (Eds Mofrad RK and Kamm RD)54. Abbreviations: Akt, protein kinase B; c-Src, tyrosine-protein kinase; FAK, focal adhesion kinase; MAP, mitogen-activated protein; NFκB, nuclear factor κB; p130Cas, Crk-associated substrate; PECAM-1, platelet endothelial cell adhesion molecule 1; Ras, small GTPase; Rho, small GTPase related to Ras; SH2, Src homology 2 domain; Shc, SH2-combining adaptor protein; VE-cadherin, vascular endothelial cadherin; VEGFR2, vascular endothelial growth factor receptor 2.