β-Arrestin2 is a critical component of the GPCR–eNOS signalosome

Significance We previously demonstrated that intrahepatic portal hypertension is caused in part by an endothelialopathy in which a number of G protein-coupled receptor (GPCR) regulatory proteins are dysregulated in injured sinusoidal endothelial cells (SECs). Here, we identified a fundamental molecular mechanism controlling eNOS function. We show that β-arrestin2 (β-Arr2) is an integral component of the eNOS signaling complex, which includes eNOS/GIT1, and that this module becomes dysregulated after injury-reduced levels of β-Arr2 lead to a reduction in eNOS phosphorylation/activation and NO production in injured SECs. The physiological and functional importance of β-Arr2 is demonstrated in vivo and ex vivo, and molecular mechanisms underlying its behavior are uncovered. These findings have important therapeutic implications for a number of vascular disorders.