Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia

Abstract

Objective-Loss-of-function mutations in genes coding for transforming growth factor-β/bone morphogenetic protein receptors and changes in nitric oxide (NO) bioavailability are associated with hereditary hemorrhagic telangiectasia and some forms of pulmonary arterial hypertension. How these abnormalities lead to seemingly disparate pulmonary pathologies remains unknown. Endoglin (Eng), a transforming growth factor-β coreceptor, is mutated in hereditary hemorrhagic telangiectasia and involved in regulating endothelial NO synthase (eNOS)-derived NO production and oxidative stress. Because some patients with pulmonary arterial hypertension harbor ENG mutations leading to haplo insufficiency, we investigated the pulmonary vasculature of Eng mice and the potential contribution of abnormal eNOS activation to pulmonary arterial hypertension. Methods and Results-Hemodynamic, histological, and biochemical assessments and X-ray micro-CT imaging of adult Eng mice indicated signs of pulmonary arterial hypertension including increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of small arteries. These findings were absent in 3-week-old Eng mice and were attributable to constitutively uncoupled eNOS activity in the pulmonary circulation, as evidenced by reduced eNOS/heat shock protein 90 association and increased eNOS-derived superoxide (O2) production in a BH4-independent manner. These changes render eNOS unresponsive to regulation by transforming growth factor-β/bone morphogenetic protein and underlie the signs of pulmonary arterial hypertension that were prevented by Tempol. Conclusion-Adult Eng mice acquire signs of pulmonary arterial hypertension that are attributable to uncoupled eNOS activity and increased O2 production, which can be prevented by antioxidant treatment. Eng links transforming growth factor/bone morphogenetic protein receptors to the eNOS activation complex, and its reduction in the pulmonary vasculature leads to increased oxidative stress and pulmonary arterial hypertension. © 2010 American Heart Association, Inc.