Mechanosensitive G_q/11 Protein-Coupled Receptors Mediate Myogenic Vasoconstriction

Myogenic vasoconstriction (Bayliss effect) is mediated by vascular smooth muscle cells (VSMCs) of small resistance arteries sensing mechanical forces. During the last three decades, several proteins have been proposed as VSMC mechanosensors. Our previous studies highlighted agonist-independent mechanical activation of G_q/11 protein-coupled receptors (G_q/11 PCRs) in VSMCs of resistance arteries. In particular, angiotensin II AT1 receptors (AT₁ Rs) emerged as mechanosensors mediating myogenic tone. Moreover, we found that the AT_1B receptor isoform was more mechanosensitive than the AT_1A receptor. Interestingly, cysteinyl leukotriene 1 receptors (CysLT₁ Rs) were up-regulated in AT₁ R-deficient arteries as an essential backup strategy to compensate for the loss of vasoconstrictor receptors. Up-regulation of CysLT₁ Rs resulted in increased myogenic tone at low intraluminal pressures resulting in hyperactivity of AT₁ R-deficient arteries. Only at high intraluminal pressures myogenic tone was reduced, thus reflecting the loss of AT₁ Rs. Further, CysLT₁ Rs were involved in myogenic vasoconstriction of wild-type arteries. Simultaneous blockade of AT₁ Rs and CysLT₁ Rs in wild-type arteries caused reduction in myogenic tone of more than 60% comparable to the application of the selective G_q/11 -protein inhibitor YM-254890. Our findings suggest that AT₁ Rs and CysLT₁ Rs are crucial mechanosensors in resistance arteries mediating 60% of myogenic vasoconstriction via the G_q/11 -protein pathway without involvement of endogenous agonists.