Rap1 in endothelial biology.

Abstract

Ubiquitously-expressed small GTPase Rap1 is a key modulator of integrin- and cadherin-regulated processes. In endothelium, Rap1 promotes angiogenesis and endothelial barrier function, acting downstream from cAMP-activated Rap1GEF, Epac. Recent in-vivo studies in mouse models have provided more information about the physiological role of Rap1 in vessel development and after birth under normal and pathologic conditions. Important molecular details of dynamic regulation of endothelial barrier are uncovered. Rap1 is not essential for initial vessel formation but is critical for vessel stabilization, as double knockout of the two Rap1 isoforms leads to hemorrhage and embryonic lethality. After development, Rap1 is not required for endothelial barrier maintenance but is critical for nitric oxide production and endothelial function. Radil and Afadin mediate Rap1 effects on endothelial barrier function by regulating connection with Rho GTPases, actomyosin cytoskeleton, and cell-cell adhesion receptors. Rap1 is critically required for nitric oxide release and normal endothelial function in vivo. Mechanistic studies lead to a novel paradigm of Rap1 as a critical regulator of endothelial cell shear stress responses and endothelial homeostasis. Increased understanding of molecular mechanisms underlying endothelial barrier regulation may identify novel pharmacological targets for retinopathies and conditions with altered endothelial barrier function or when increased endothelial barrier is desired.