Lessons from the endothelial junctional mechanosensory complex

Abstract

Mechanotransduction plays a key role in both normal physiology and in diseases such as cancer, atherosclerosis and hypertension. Nowhere is this more evident than in the vascular system, where fluid shear stress from blood flow plays a critical role in shaping the blood vessels and in determining their function and dysfunction. Responses to flow are mediated in part by a complex of proteins comprised of PECAM-1, VE-cadherin and VEGFR2 at endothelial cell-cell junctions; all proteins that clearly have other, non-mechanical functions. We review recent progress toward understanding the functions and mechanisms of mechanotransduction by this complex and suggest some principles that may apply more broadly.

Figure 1.. Potential mechanism for assembly of the mecanosensory complex

a) VE-cadherin (vascular-endothelial cadherin) and PECAM-1 (platelet endothelial cell adhesion molecule-1) engage in homophilic interactions at intracellular junctions in cells cultured under static conditions. b) When cells are exposed to fluid flow, cells are exposed to a shear stress force. At the onset of shear stress, a src-family kinase (evidently fyn) is activated by phosphorylation and is recruited to and phosphorylates PECAM-1 c) Once PECAM-1 is phosphorylated, VE-cadherin recruits VEGFR2 (vascular endothelial growth factor receptor 2) to the complex. VEGFR2 is then phosphorylated by the src kinase and activates downstream pathways such as Akt and MAP kinases. The specific details of how the complex is assembled (including other binding partners) is currently unknown. Abbreviations: PECAM, platelet endothelial cell adhesion molecule; VE, vascular-endothelial; VEGFR, vascular endothelial growth factor receptor.