Abstract 378: Endothelial Cell Hypoxia-inducible Factor (HIF) Activity is Necessary for Right Ventricular Remodeling in a Murine Model of Chronic-hypoxic Pulmonary Hypertension

Introduction: Pulmonary hypertension induced myocardial remodeling is required to minimize RV wall stress as pulmonary arterial pressures increase. Myocardial angiogenesis is presumed to play an integral role in early RV remodeling, though molecular regulators remain undefined. Endothelial cell (EC) expression of HIF-1 is necessary for adaptive LV remodeling during chronic pressure overload, with loss of EC-specific HIF-1 activity associated with reduced LV capillary density. We hypothesized that EC HIF activity may also be necessary for adaptive RV remodeling and angiogenesis in a model of chronic RV pressure overload. Methods: We used a murine model of chronic hypoxic pulmonary hypertension (CH-PH) to induce RV remodeling. Conditional transgenic mice lacking expression of the obligate HIF-1α/HIF-2α co-factor ARNT (aryl hydrocarbon receptor nuclear translocator) in Tie2+ lineage cells ( ARNT fl/fl ; Tie2-Cre +/- ) and ARNT fl/fl ;Tie2-Cre -/- controls were exposed to normobaric hypoxia (10% FiO 2 ) for 1-5 weeks. We measured RV hypertrophy (RVH), RV systolic pressure (RVSP), and myocardial EC proliferation (flow cytometry) as a marker for sprouting angiogenesis. Results: After three weeks of CH-PH, RVH was observed in ARNT fl/fl ;Tie2-Cre -/- control mice, as anticipated (0.332±0.02 vs. 0.231±0.02; P < 0.05). CH-PH induced RVH in ARNT fl/fl ;Tie2-Cre -/- mice was associated with an early (1 week) increase in RV EC proliferation (vs. LV, 4.5±1.3% vs.1.8±0.5%; P < 0.05). Conversely, ARNT fl/fl ; Tie2 - Cre +/- mice did not develop RVH after 3 weeks of CH ( 0.222±0.01 vs. 0.241±0.02; P = NS), and early RV EC proliferation was attenuated (vs. LV, 2.9±1.2% vs. 1.5±0.3%; P = NS). Despite similar increases in CH-PH induced RVSP after 3 weeks, after 5 weeks RVSP normalized in ARNT fl/fl ; Tie2 - Cre +/- mice, but remained elevated in ARNT fl/fl ;Tie2-Cre -/- controls. Conclusions: These preliminary findings confirm that EC-specific HIF activity is necessary for CH-PH induced RVH, and suggest that reduced EC proliferation (and potentially angiogenesis) may contribute to abrogated RV remodeling in ARNT fl/fl ; Tie2 - Cre +/- mice. We hypothesize that late normalization of RVSP in these mice may be indicative of premature RV failure.