Cysteinyl Leukotriene 1 Receptors as Novel Mechanosensors Mediating Myogenic Tone Together With Angiotensin II Type 1 Receptors—Brief Report

Objective— Myogenic vasoconstriction is mediated by vascular smooth muscle cells of resistance arteries sensing mechanical stretch. Angiotensin II AT 1 receptors and in particular AT 1B Rs in murine vascular smooth muscle cells have been characterized as mechanosensors that cannot fully account for myogenic vasoconstriction observed. Therefore, we aimed at uncovering novel vascular mechanosensors by expression profiling and functional characterization of candidate proteins. Approach and Results— Analyzing myogenic tone of isolated murine mesenteric arteries of AT 1A and AT 1B receptor double gene-deficient (AT 1A/1B −/− ) mice ex vivo, we observed a decreased myogenic tone at high intraluminal pressures and an unexpected hyper-reactivity at low intraluminal pressures because of upregulation of cysteinyl leukotriene 1 receptors (CysLT 1 Rs). Pharmacological blockade of CysLT 1 Rs with pranlukast significantly reduced myogenic tone not only in AT 1A/1B −/− but also in wild-type arteries. In wild-type arteries, additional blockade of angiotensin II AT 1 receptors with candesartan resulted in an additive reduction of myogenic tone. Furthermore, calcium imaging experiments were performed with fura-2–loaded human embryonic kidney 293 cells overexpressing CysLT 1 Rs and with isolated mesenteric vascular smooth muscle cells. Hypo-osmotically induced membrane stretch provoked calcium transients that were significantly reduced by pranlukast. Incubations of isolated mesenteric vascular smooth muscle cells with the 5-lipoxygenase inhibitor zileuton had no effect. Furthermore, the G q/11 -protein inhibitor YM 254890 profoundly reduced myogenic tone to the same extent as induced by the application of pranlukast plus candesartan. Conclusions— Here, we identify a novel, hitherto unappreciated role of CysLT 1 Rs in vascular regulation. We identified CysLT 1 Rs as novel mechanosensors in the vasculature involved in myogenic vasoconstriction. Moreover, our findings suggest that myogenic tone is determined by AT 1 and CysLT 1 receptors acting together as mechanosensors via G q/11 -protein activation.