Place: Kleiner Physik-Hörsaal, Geschwister-Scholl-Platz
Date: 18.12.09, Time: 15:30 h
Mechanosensation in vascular smooth muscle cells
Prof. Dr. med. Thomas Gudermann
Walther-Straub-Institut für Pharmakologie und Toxikologie, LMU
In spite of the central physiological role of the myogenic response, the underlying signaling pathways and the identity of mechanosensors in vascular smooth muscle are still unclear. We provide experimental evidence to show that membrane stretch does not primarily gate mechanosensitive TRP ion channels, but leads to agonist-independent activation of Gq/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 β-arrestin. Agonist-independent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT1 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 AT1 receptor agonist losartan independently of angiotensin II secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signaling. These findings suggest that Gq/11-coupled receptors function as sensors of membrane stretch in vascular smooth muscle cells. Further studies are required to gain a deeper knowledge about the mechanisms underlying the conversion of mechanical force into a biological response.