Abstract 16970: Strain-specific Differences in the Response to SU5416 in the Rat Model of Severe Pulmonary Arterial Hypertension
INTRODUCTION: Inhibition of VEGFR2 with SU5416 (SU), in combination with chronic hypoxia (CH) causes severe, irreversible pulmonary arterial hypertension (PAH) in rats associated with complex intimal and plexiform lesions. We assessed the response to SU in the presence and absence of CH in several different strains of rats to explore the potential importance of genetic background in the development of the severe PAH phenotype.
METHODS: The response to a single subcutaneous injection of SU5416 (SU: 20mg/kg) or vehicle (Control) was assessed in 6-week-old Sprague-Dawley (SD) wild type rats compared with Lewis and Fischer rats with and without exposure to 3-weeks of CH (8~10% oxygen) with end-studies at 7-8 weeks after SU or vehicle injection.
RESULTS: SD rats exhibited severe PAH even after treatment with SU alone (n=19) with marked increases in right ventricular systolic pressure (RVSP: 88±8 mmHg) accompanied by RV remodeling (RV/LV+septum: 61±5%) compared to control (n=17) SD rats (RVSP: 29±0.5 mmHg and RV/LV+septum: 27±0.5% ; p<0.0001). The combination of SU+CH (n=14) did not result in any further increases in RVSP (81± 6 mmHg) or RV hypertrophy (RV/LV+septum:59±3%) in these animals. In contrast, Fischer rats showed no significant response to SU alone, but developed a severe PAH phenotype in response to SU+CH (RVSP: 107±15 mmHg; RV/LV+septum: 59±5%); whereas, Lewis rats were least responsive to SU+CH (RVSP: 48±3 mmHg). Interestingly, the highest mortality was in Fischer rats exposed to SU+CH (88%), compared to SD rats treated by SU with and without CH (50% and 31%, respectively).
CONCLUSIONS: These data identify important strain differences that impact on the severity of PAH and the requirement for concomitant CH following inhibition of VEGFR2. Although Fischer rats were less susceptible to SU-induced PAH than SD rats, they appear to exhibit higher mortality, possible due to differences in RV adaptation in response to the increased hemodynamic load.
- © 2013 by American Heart Association, Inc.