Stimulatory G-Protein alpha Subunit Modulates Endothelial Cell Permeability Through Regulation of Plasmalemma Vesicle-Associated Protein

Endothelial cell leakage occurs in several diseases. Intracellular junctions and transcellular fashion are involved. The definite regulatory mechanism is complicated and not fully elucidated. The alpha subunit of the heterotrimeric G-stimulatory protein (Gs alpha) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of Gs alpha in the endothelial barrier remains unclear. In this study, mice with knockout of endothelial-specific Gs alpha (Gs alpha(ECKO)) were generated by crossbreeding Gs alpha(flox/flox) mice with Cdh5-CreER(T2) transgenic mice, induced in adult mice by tamoxifen treatment. Gs alpha(ECKO) mice displayed phenotypes of edema, anemia, hypoproteinemia and hyperlipoproteinemia, which indicates impaired microvascular permeability. Mechanistically, Gs alpha deficiency reduces the level of endothelial plasmalemma vesicle-associated protein (PLVAP). In addition, overexpression of Gs alpha increased phosphorylation of cAMP response element-binding protein (CREB) as well as the mRNA and protein levels of PLVAP. CREB could bind to the CRE site of PLVAP promoter and regulate its expression. Thus, Gs alpha might regulate endothelial permeability via cAMP/CREB-mediated PLVAP expression.