Sex Differences in Pulmonary Vascular Remodeling: The Role of Estrogen

Pulmonary arterial hypertension (PAH) is a rare and rapidly fatal disease that is characterized by distal pulmonary arterial narrowing, proximal pulmonary arterial stiffening and eventual right ventricular failure. PAH strikes women four times more often than men but paradoxically women with PAH have better survival rates than men with PAH. We hypothesized that estrogen attenuates proximal arterial stiffening, which imparts hemodynamic and energetic benefits to right ventricular (RV) function. To test this hypothesis, female mice were ovariectomized and treated with estrogen or placebo. PAH was induced using a vascular endothelial growth factor receptor inhibitor (SUGEN) and chronic hypoxia (SuHx). Our results demonstrate that estrogen protects RV function in PAH directly by stimulating RV contractility and indirectly by limiting proximal pulmonary artery stiffening. These results underscore the therapeutic potential of estrogen in PAH and provide a biomechanical mechanism for delayed disease progression and better outcome in female PAH patients.