title: Deletion of STAT5a/b in vascular smooth muscle abrogates the male bias in hypoxic pulmonary hypertension in mice: implications in the human disease.
abstract: Chronic hypoxia typically elicits pulmonary hypertension (PH) in mice with a male-dominant phenotype. There is an opposite-sex bias in human PH, with a higher prevalence in women, but greater survival (the "estrogen paradox"). We investigated the involvement of the STAT5a/b species, previously established to mediate sexual dimorphism in other contexts, in the sex bias in PH. Mice with heterozygous or homozygous deletions of the STAT5a/b locus in vascular smooth muscle cells (SMCs) were generated in crosses between STAT5a/b(fl/fl) and transgelin (SM22α)-Cre(+/+) parents. Wild-type (wt) males subjected to chronic hypoxia showed significant PH and pulmonary arterial remodeling, with wt females showing minimal changes (a male-dominant phenotype). However, in conditional STAT5(+/-) or STAT5(-/-) mice, hypoxic females showed the severest manifestations of PH (a female-dominant phenotype). Immunofluorescence studies on human lung sections showed that obliterative pulmonary arterial lesions in patients with idiopathic pulmonary arterial hypertension (IPAH) or hereditary pulmonary arterial hypertension (HPAH), both male and female, overall had reduced STAT5a/b, reduced PY-STAT5 and reduced endoplasmic reticulum (ER) GTPase atlastin-3 (ATL3). Studies of SMCs and endothelial cell (EC) lines derived from vessels isolated from lungs of male and female IPAH patients and controls revealed instances of coordinate reductions in STAT5a, STAT5b and ATL3 in IPAH-derived cells, including SMCs and ECs from the same patient. Taken together, these data provide the first definitive evidence for a contribution of STAT5a/b to the sex bias in PH in the hypoxic mouse and implicate reduced STAT5 in the pathogenesis of the human disease.
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: John G
authors.initials: JG
authors.lastname: Edwards
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Yester
authors.initials: Y
authors.lastname: Skayian
authors.affiliation: Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.affiliation: Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York, United States of America.|Department of Medicine, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Pravin B
authors.initials: PB
authors.lastname: Sehgal
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D009124:Muscle Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; C058992:Tagln protein, mouse; D020558:GTP Phosphohydrolases; C529895:ATL3 protein, human