title: PGC-1α dictates endothelial function through regulation of eNOS expression.
abstract: Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1α sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1α EC TG mice were protected. Mechanistically, PGC-1α promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1α expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor α (ERRα) is required to coordinate the PGC-1α -induced eNOS expression. In conclusion, endothelial PGC-1α expression protects from vascular dysfunction by promoting NO• bioactivity through ERRα induced expression of eNOS.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Craige
authors.affiliation: Department of Cardiology Medizinische Klinik und Poliklinik Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Shenghe
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Cardiology Medizinische Klinik und Poliklinik Universitätsmedizin Mainz, Mainz, Germany.|University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Mayur M
authors.initials: MM
authors.lastname: Contractor
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Cardiology Medizinische Klinik und Poliklinik Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000804:Angiotensin II; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse