title: The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype.
abstract: Although female predominance in the development of all types of pulmonary hypertension (PH) is well established, many clinical studies have confirmed that females have better prognosis and higher survival rate than males. There is no clear explanation of why sex influences the pathogenesis and progression of PH. Using a rat angioproliferative model of PH, which closely resembles the primary pathological changes observed in humans, we evaluated the role of sex in the development and progression of PH. Female rats had a more pronounced increase in medial thickness in the small pulmonary arteries. However, the infiltration of small pulmonary arteries by inflammatory cells was found only in male rats, and this corresponded to increased myeloperoxidase activity and abundant adventitial and medial fibrosis that were not present in female rats. Although the level of right ventricle (RV) peak systolic pressure was similar in both groups, the survival rate in male rats was significantly lower. Moreover, male rats presented with a more pronounced increase in RV thickness that correlated with diffuse RV fibrosis and significantly impaired right cardiac function. The reduction in fibrosis in female rats correlated with increased expression of caveolin-1 and reduced endothelial nitric oxide synthase-derived superoxide. We conclude that, in the pathogenesis of PH, female sex is associated with greater remodeling of the pulmonary arteries but greater survival. Conversely, in males, the development of pulmonary and cardiac fibrosis leads to early and severe RV failure, and this may be an important reason for the lower survival rate among males.
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA ; These authors contributed equally to this study.
authors.forename: Olga
authors.initials: O
authors.lastname: Rafikova
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA ; These authors contributed equally to this study.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Mary Louise
authors.initials: ML
authors.lastname: Meadows
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Kangath
authors.affiliation: Institute of Pathology, Hannover Medical School, Hanover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
keywords: caveolin-1; nitric oxide synthase; oxidative stress; superoxide