title: Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction.
abstract: Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH(-/-) mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH(-/-) mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension.
authors.affiliation: Institutes of Physiology I and Molecular Psychiatry, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.forename: Michaela
authors.initials: M
authors.lastname: Matthey
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.forename: Raissa
authors.initials: R
authors.lastname: Lerner
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D002853:Chromatography, Liquid; D017931:DNA Primers / Q000235:genetics; D063388:Endocannabinoids / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D017931:DNA Primers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide
keywords: cannabinoid; pulmonary vascular tone