title: Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension.
abstract: Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways. Earlier reports have shown that diacylglycerol produced during calcium signal generation can be converted to an endocannabinoid, 2-arachidonoylglycerol (2-AG). Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension. Rat and mouse aortic rings were examined by myography. Vascular expression of CB1R was demonstrated with immunohistochemistry. Rat aortic vascular smooth muscle cells (VSMCs) were cultured for calcium measurements and 2-AG-determination. Inhibition or genetic loss of CB1Rs enhanced vasoconstriction induced by angiotensin II (AngII) or phenylephrine (Phe), but not by prostaglandin(PG)F2α. AngII-induced vasoconstriction was augmented by inhibition of diacylglycerol lipase (tetrahydrolipstatin) and was attenuated by inhibition of monoacylglycerol lipase (JZL184) suggesting a functionally relevant role for endogenously produced 2-AG. In Gαq/11-deficient mice vasoconstriction was absent to AngII or Phe, which activate Gq/11-coupled receptors, but was maintained in response to PGF2α. In VSMCs, AngII-stimulated 2-AG-formation was inhibited by tetrahydrolipstatin and potentiated by JZL184. CB1R inhibition increased the sustained phase of AngII-induced calcium signal. Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice. These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation. Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone. Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.
authors.affiliation: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Szekeres
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: György L
authors.initials: GL
authors.lastname: Nádasy
authors.affiliation: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Turu
authors.affiliation: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Soltész-Katona
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Benyó
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Ruisanchez
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Szabó
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Takáts
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.affiliation: Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
authors.forename: Zsuzsanna E
authors.initials: ZE
authors.lastname: Tóth
authors.affiliation: Department of Physiology, Semmelweis University, Budapest, Hungary; MTA-SE Laboratory of Molecular Physiology, Budapest, Hungary. Electronic address: hunyady@eok.sote.hu.
authors.forename: László
authors.initials: L
authors.lastname: Hunyady
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D015237:Dinoprost / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D005989:Glycerides / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007783:Lactones / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077403:Orlistat; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D007783:Lactones; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D000804:Angiotensin II; D010656:Phenylephrine; C094503:glyceryl 2-arachidonate; D000077403:Orlistat; D015237:Dinoprost; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium
keywords: Angiotensin II; Blood pressure; Calcium signaling; Endocannabinoid; G protein-coupled receptor; Vasoconstriction