title: Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure.
abstract: The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ∼90-120 μm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl-β-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high-fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild-type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Istvan
authors.initials: I
authors.lastname: Czikora
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Attila
authors.initials: A
authors.lastname: Feher
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Fulton
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia zbagi@gru.edu.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D021941:Caveolae / Q000378:metabolism; D051243:Caveolin 2 / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D014655:Vascular Resistance; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D051243:Caveolin 2; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II
keywords: angiotensin receptor; arteriole; caveolae; hypertension; obesity; trafficking