Deletion of STAT5a/b in Vascular Smooth Muscle Abrogates the Male Bias in Hypoxic Pulmonary Hypertension in Mice: Implications in the Human Disease

Yang-Ming Yang, Huijuan Yuan, John G. Edwards, Yester Skayian, Kanta Ochani, Edmund J. Miller, Pravin B. Sehgal

Chronic hypoxia typically elicits pulmonary hypertension (PH) in mice with a male-dominant phenotype. There is an opposite sex-bias in human PH with higher prevalence in women, but greater survival (the "estrogen paradox"). We investigated the involvement of 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 (SMC) 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 -/- 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 or hereditary pulmonary arterial hypertension (IPAH or HPAH), both male and female, overall, had reduced STAT5a/b, reduced PY-STAT5 and reduced endoplasmic reticulum (ER) GTPase atlastin-3 (ATL3). Studies of SMC 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 in 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.