Despite the central physiological function of the myogenic response, the underlying signalling pathways and the identity of mechanosensors in vascular smooth muscle (VSM) are still elusive. In contrast to present thinking, we show that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist-independent activation of G q/11 -coupled receptors, which subsequently signal to TRPC channels in a G protein-and phospholipase C-dependent manner. Mechanically activated receptors adopt an active conformation, allowing for productive G protein coupling and recruitment of b-arrestin. Agonistindependent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT 1 angiotensin II receptor density in mechanically unresponsive rat aortic A7r5 cells resulted in mechanosensitivity. Myogenic tone of cerebral and renal arteries is profoundly diminished by the inverse angiotensin II AT 1 receptor agonist losartan independently of angiotensin II (AII) secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signalling-2. These findings suggest that G q/11 -coupled receptors function as sensors of membrane stretch in VSM cells.

The distal steps of the signalling cascade leading to myogenic constriction in vascular smooth muscle cells have been well investigated, while sensing and the proximal steps are enigmatic. Here we show that mechanical membrane stretch and osmotic cell swelling agonist‐independently activate Gq‐coupled receptors, and subsequently TRPC channels. Using BRET, β‐arrestin was shown to be recruited to the receptor by membrane stretch in a way similar to that seen on agonist stimulation. Simultaneous agonist and mechanical stimulation led to a leftward shift of the angiotensin II‐concentration response curve. Receptor activation and the subsequent signalling cascade could be blocked at different levels. We show that Gq‐coupled receptors like AT1 angiotensin II and V1A vasopressin receptors are activated by membrane stretch dependent on their receptor density. Elevated expression levels of AT1 receptors in A7r5 cells, as well as high endogenous expression levels in renal vascular smooth muscle cells were sufficient for mechanosensivity. In rat cerebral and mouse renal arteries, myogenic tone was profoundly diminished by incubation with the AT1 receptor inverse agonist losartan. Thus, Gq‐coupled receptors are important components of the mechanosensory complex in vascular smooth muscle cells.