C26-12 Inhibition of Vegf-a With a Monoclonal Neutralizing Antibody Rescues Angio-obliterative Experimental Pulmonary Hypertension

Abstract Introduction Dysfunctional angiogenesis is one of the hallmark pathological features of pulmonary arterial hypertension (PAH). Vascular endothelial growth factor (VEGF) is a well-characterized proangiogenic factor that induces proliferation and migration of endothelial cells (ECs). Prior studies have reported elevated plasma VEGF levels, and increased VEGF expression in vascular lesions in PAH. There is conflicting data on whether VEGF is a pathogenic or protective molecule in PAH. Hypothesizing that VEGF is a driver of PAH, we tested the impact of a neutralizing anti-VEGFA monoclonal antibody (B20) in a rodent model of angio-obliterative experimental pulmonary hypertension (PH). Methods B20-4.1.1, a monoclonal antibody recognizing rodent VEGF-A, was administered to adult Sprague-Dawley rats as prophylaxis during disease induction, or as rescue therapy following experimental PH with 3 weeks of SU5416 (Sugen, 20 mg/kg, s.c.) and hypoxia (FIO2=10%). Rats received B20-4.1.1 (5 mg/kg twice weekly) for three weeks during prophylaxis or treatment, isotype control antibody, or macitentan (30 mg/kg/d) for three weeks. Right ventricular systolic pressure (RVSP), Fulton’s Index, and histomorphometry of lung vessel remodeling were assessed using invasive hemodynamics, and immunofluorescence. Results SuHx rats developed moderate-severe PH with SU-Hx. Prophylactic treatment with B20-4.1.1 elicited a trend towards improved RVSP and Fulton’s index as compared to vehicle treatment in SU-Hx rats, whereas rescue therapy significantly attenuated RVSP and Fulton Index, compared to isotype and normoxic controls. The effects of B20-4.1.1 were comparable to that of macitentan, an approved endothelin receptor antagonist. Immunofluorescence revealed significantly reduced muscularization in SuHx rats receiving rescue therapy with B20-4.1.1. Conclusion These results support the therapeutic potential of VEGF-A antagonism in PAH, based on its efficacy in an angio-obliterative experimental model of PH, with efficacy resembling a standard-of-care therapy. The therapeutic effects were more evident when administered after the onset of experimental PH than when given prophylactically, suggesting dynamic roles of VEGF-A during the progression of experimental PH. This abstract is funded by: NIH