Endocannabinoid-mediated modulation of G protein-coupled receptor signaling-induced vasoconstriction and hypertension.

Szekeres, Mária and Nádasy, György László and Turu, Gábor and Soltész-Katona, Eszter and Benyó, Zoltán and Ruisanchez, Éva and Szabó, Eszter and Takáts, Zoltán and Bátkai, Sándor and Tóth, Zsuzsanna E. and Hunyady, László (2015) Endocannabinoid-mediated modulation of G protein-coupled receptor signaling-induced vasoconstriction and hypertension. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 403C. pp. 46-56. ISSN 0303-7207

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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)F2alpha. 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 Galphaq/11-deficient mice vasoconstriction was absent to AngII or Phe, which activate Gq/11-coupled receptors, but was maintained in response to PGF2alpha. 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.

Item Type: Article
Subjects: Q Science / természettudomány > QP Physiology / élettan
Depositing User: MTMT SWORD
Date Deposited: 09 Feb 2015 14:12
Last Modified: 09 Feb 2015 14:12

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