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 AT1 receptors and in particular AT1BRs 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.


RESULTS
Analyzing myogenic tone of isolated murine mesenteric arteries of AT1A and AT1B receptor double gene-deficient (AT1A/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 (CysLT1Rs). Pharmacological blockade of CysLT1Rs with pranlukast significantly reduced myogenic tone not only in AT1A/1B (-/-) but also in wild-type arteries. In wild-type arteries, additional blockade of angiotensin II AT1 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 CysLT1Rs 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 Gq/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 CysLT1Rs in vascular regulation. We identified CysLT1Rs as novel mechanosensors in the vasculature involved in myogenic vasoconstriction. Moreover, our findings suggest that myogenic tone is determined by AT1 and CysLT1 receptors acting together as mechanosensors via Gq/11-protein activation.
From the Walther Straub Institute of Pharmacology and Toxicology (U.S., S.B., T.G., M.MyS.), Ludwig Maximilians University of Munich, Munich, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (T.G., M.MyS.), Munich, Germany.
Ursula
U
Storch
From the Walther Straub Institute of Pharmacology and Toxicology (U.S., S.B., T.G., M.MyS.), Ludwig Maximilians University of Munich, Munich, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (T.G., M.MyS.), Munich, Germany.
Stephanie
S
Blodow
From the Walther Straub Institute of Pharmacology and Toxicology (U.S., S.B., T.G., M.MyS.), Ludwig Maximilians University of Munich, Munich, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (T.G., M.MyS.), Munich, Germany. mederos@lrz.uni-muenchen.de thomas.gudermann@lrz.uni-muenchen.de.
Thomas
T
Gudermann
From the Walther Straub Institute of Pharmacology and Toxicology (U.S., S.B., T.G., M.MyS.), Ludwig Maximilians University of Munich, Munich, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (T.G., M.MyS.), Munich, Germany. mederos@lrz.uni-muenchen.de thomas.gudermann@lrz.uni-muenchen.de.
Michael
M
Mederos Y Schnitzler
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure; D020013:Calcium Signaling; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008638:Mesenteric Arteries / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
C000595374:AGTR1b protein, mouse; C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D020024:Leukotriene Antagonists; D044140:Receptor, Angiotensin, Type 1; D018077:Receptors, Leukotriene; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C083169:leukotriene D4 receptor
G-protein–coupled receptors