Deletion of STAT5a/b in Vascular Smooth Muscle Abrogates the Male Bias in Hypoxic Pulmonary Hypertension in Mice: Implications in the Human Disease
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/bfl/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.
We thank Lothar Hennighausen (National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, USA) for a breeder pair of the STAT5a/bfl/fl mice and Rubin M Tuder (University of Colorado-Denver, Aurora, CO, USA) for the human lung sections (controls and IPAH). Additional lung sections, SMCs and ECs derived from lungs of male and female IPAH patients and controls were provided under the PHBI from the Baylor College of Medicine, The Cleveland Clinic Foundation, University of Alabama at Birmingham, Stanford University, Vanderbilt University, University of California at San Diego, Duke University, University of Michigan, University of Colorado-Denver, Allegheny General Hospital, and University of Pennsylvania. Funding for PHBI is provided by the Cardiovascular Medical Research and Education Fund (CMREF). This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-087176 (to PB Sehgal), HL-114509 (to PB Sehgal) and HL-111469 (EJ Miller).
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