090 Inhibition of VEGFR2 is Sufficient to Produce Severe Plexogenic Pulmonary Arterial Hypertension in Rats

Abstract

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance due to obliteration of the small arterioles of the lung. Sugen 5416 (SU), a VEGFR2 inhibitor, has been reported to cause endothelial cell (EC) apoptosis resulting in severe PAH in chronically hypoxic (CH) rats, characterized by complex intimal and plexiform lesions. Recently, it was suggested that immune deficient, nude rats were more susceptible to SU, demonstrating a severe PAH phenotype even in the absence CH. To establish the relative importance of hypoxia for development of severe PAH after a single subcutaneous injection of SU5416 depending on the background rat strain. Wild type (WT) Sprague Dawley or nude (6-week-old) rats were randomly divided into 4 groups: a single intraperitoneal injection of vehicle (Control) or SU5416 (20mg/kg) (SU); 3 weeks of CH (10% oxygen) or SU injection combined with 3 weeks of CH (SU+CH). After 3 weeks, the CH groups were returned to normoxia for an additional 5 weeks. Echocardiography, hemodynamics, structural remodeling and histological examinations were performed at 8 weeks for all groups. As previously reported, SU+CH produced severe PAH in WT rats with right ventricular systolic pressure (RVSP) approaching to systemic levels (80±8 mm Hg, Figure); whereas rats exposed to CH alone showed more modest increases in RVSP (40±2 mmHg). In the absence of CH, SU alone induced a PAH in nude rats (RVSP 55±9 mm Hg). Surprisingly, SU alone also produced a marked and significant increase in RVSP in WT rats (84±9 mmHg) compared to vehicle control (29±1 mm Hg, p<.0001). The ratio of RV/LV+Septum was increased to a similar extent in both SU and SU+CH groups (p<.0001 vs. vehicle control). Moreover, mortality was increased in the SU and SU+CH groups (47% vs. 29%; respectively). Echocardiographic assessments confirmed the development of severe PAH in both SU groups with decreased PA acceleration time (PAAT) and increased RV free wall thickness (RVWT) (all p<0.01); again there were no significant differences between SU alone and SU+CH group. Histological analysis showed that both SU alone and SU+CH group developed severe pulmonary arteriopathy, including neointimal occlusion and plexiform-like lesions. These data show that inhibition of VEGFR2 by a single injection of SU5416 was sufficient to induce severe and irreversible PAH in WT rats, even in the absence of CH. These data underscore the critical importance of EC apoptosis a necessary and sufficient trigger for experimental PAH.