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To investigate the functional role of TRPC6 channels in vascular smooth muscle cells, TRPC6 gene-deficient (TRPC6-/-) mice were used. In cerebral arteries disruption of the TRPC6 gene caused an enhanced responsiveness to intravascular pressure with the onset of myogenic vasoconstriction at lower pressures. Electrophysiological whole-cell measurements from freshly-isolated TRPC6-/- cerebral arteries smooth muscle cells revealed an increase in basal current densities compared to wildtype. Furthermore, currents activated by DAG analogs were larger in TRPC6-/- mice. In addition, the membrane potential of TRPC6-/- smooth muscle cells was more depolarized, suggesting that voltage-gated calcium channels are more likely to be activated. The increases in vascular tone and in current densities in TRPC6-/- mice might be due to the compensatory gene expression of TRPC3. The data on TRPC6-/- mice provide evidence that TRPC6-channel proteins play a distinctive role in the control of vascular smooth muscle tone. Since the nature of the mechanosensors in the signalling cascade leading to myogenic vasoconstriction are still elusive, the mechanosensitivity of individual steps in the signalling cascade was examined. As a first step, the mechanosensitivity of TRPC6 was tested. Neither suction-induced nor osmotically-induced membrane stretch caused the rapid activation of TRPC6 which would be expected for a mechanosensitive channel. Instead, Gq/11 protein-coupled receptors were identified as the mechanosensors in vascular smooth muscle cells. These receptors initiate the classical signalling cascade leading to a PLC-dependent activation of the DAG-sensitive TRPC3/6/7-channel family. Subsequent membrane depolarisation activates voltage-gated L-type calcium channels, which are the decisive components for myogenic vasoconstriction. Osmotically-induced membrane stretch, as well as direct membrane stretch either by applying a positive pipette pressure or by vertically shifting the patch pipette, caused agonist-independent receptor activation. The following signalling cascade could be blocked at the levels of the G protein und the PLC. Furthermore, specific receptor antagonists and inverse agonists suppressed mechanically-induced receptor activation. Membrane stretch induced active receptor conformations like those that occur upon agonist stimulation which resulted in G protein coupling and receptor desensitisation by the recruitment of β-arrestin. Additional overexpression of Angiotensin II AT1 receptors (AT1R) in mechanically-unresponsive A7r5 cells from rat aorta conferred mechanosensitivity on the cells, indicating that this property depends on the receptor density. Isolated smooth muscle cells from myogenic renal arterioles had a high endogenous density of the AT1R sufficient for receptor activation in response to osmotically-induced membrane stretch. Receptor activation was profoundly diminished by the inverse agonist losartan. Likewise, in rat cerebral arteries myogenic tone was strongly decreased by losartan in the absence of endogenously-produced Angiotensin II. These findings suggest that Gq/11-coupled receptors function agonist-independently as mechanosensors in vascular smooth muscle cells.