The Angiotensin II Type‐1 Receptor Is a Mechanosensor in Cerebral Parenchymal Arteriole Smooth Muscle Cells

Abstract

Angiotensin II type 1 receptors (AT1R) have been linked to mechanosensivity in cardiomyocytes, mainly through activation of a β2-arrestin signaling pathway. AT1Rs are also involved in sensation of intraluminal pressure by vascular smooth muscle cells. However, it is not known if the AT1R is a mechanosensor in cerebral parenchymal arterioles (PA), a highly specialized vasculature in which small alterations in myogenic reactivity can have profound effects on blood flow and neurovascular coupling. We hypothesized that AT1Rs are mechanosensors in cerebral arteries and arterioles, acting through β-arrestin signaling to cause myogenic constriction. Anterior cerebellar arteries (ACA) from C57Bl/6J mice were isolated and pressurized. Myogenic reactivity was reduced after exposure to the AT1R antagonist losartan. The biased AT1R agonist peptide TRV120023, a selective activator of the β-arrestin pathway, caused a small yet significant constriction (-5.9±2.9 μm, p<0.05) that was inhibited by pre-incubation with losartan. Incubation with a scrambled peptide had no effect. Myogenic reactivity of PA was also reduced after exposure to losartan. To assess if local production of angiotensin II plays a role in AT1R-dependent myogenic reactivity, PA were incubated with the angiotensin-converting enzyme inhibitor captopril. There was no difference in myogenic reactivity of PA after incubation with captopril. These data suggest that: 1) The AT1R is a smooth muscle cell mechanosensor in large cerebral pial arteries and parenchymal arterioles, through a mechanism that is not dependent on local angiotensin II production; and 2) AT1R-dependent activation of β-arrestin signaling causes a small constriction of the ACA but does not fully account for myogenic reactivity.