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.

Abstract-Periadventitial adipose tissue produces vasoactive substances that influence vascular contraction. Earlier studies addressed this issue in aorta, a vessel that does not contribute to peripheral vascular resistance. We tested the hypothesis that periadventitial adipose tissue modulates contraction of smaller arteries more relevant to blood pressure regulation. We studied mesenteric artery rings surrounded by periadventitial adipose tissue from adult male Sprague-Dawley rats. The contractile response to serotonin, phenylephrine, and endothelin I was markedly reduced in intact vessels compared with vessels without periadventitial fat. The contractile response to U46619 or depolarizing high K ϩ -containing solutions (60 mmol/L) was similar in vessels with and without periadventitial fat. The K ϩ channel opener cromakalim induced relaxation of vessels precontracted by serotonin but not by U46619 or high K ϩ -containing solutions (60 mmol/L), suggesting that K ϩ channels are involved. The intracellular membrane potential of smooth muscle cells was more hyperpolarized in intact vessels than in vessels without periadventitial fat. Both the anticontractile effect and membrane hyperpolarization of periadventitial fat were abolished by inhibition of delayed-rectifier K ϩ (K v ) channels with 4-aminopyridine (2 mmol/L) or 3,4-diaminopyridine (1 mmol/L). Blocking other K ϩ channels with glibenclamide (3 mol/L), apamin (1 mol/L), iberiotoxin (100 nmol/L), tetraethylammonium ions (1 mmol/L), tetrapentylammonium ions (10 mol/L), or Ba 2ϩ (3 mol/L) had no effect. Longitudinal removal of half the perivascular tissue reduced the anticontractile effect of fat by almost 50%, whereas removal of the endothelium had no effect. We suggest that visceral periadventitial adipose tissue controls mesenteric arterial tone by inducing vasorelaxation via K v channel activation in vascular smooth muscle cells. Key Words: muscle, smooth Ⅲ mesenteric arteries Ⅲ obesity Ⅲ hypertension, obesity P eriadventitial adipose tissue is routinely removed for contraction studies on isolated blood vessels. Soltis and Cassis demonstrated that periadventitial fat significantly attenuates vascular responsiveness of rat isolated aortic rings to norepinephrine. 1 We confirmed the inhibitory action of periadventitial fat on aortic contraction. However, we also found that the effect is antagonized by depolarizing external high K ϩ solutions and partly by glibenclamide, suggesting that the anticontractile effects of fat are mediated in part by opening of ATP-dependent K ϩ (K ATP ) channels in aortic smooth muscle cells. 2 The action was not dependent on NO synthesis or endothelium. The anticontractile effects did not require the cyclooxygenase or P450 pathway, activation of adenosine receptors, or functional leptin receptors. 2 However, we found that relaxation was induced by a transferable adipocytederived relaxing factor (ADRF) released from periadventitial adipose tissue. 2 The results were not obtained in vessels that contribute to peripheral vascular re...