Abstract 19017: Sex Differences in Severe Pulmonary Arterial Hypertension Produced by SU5416 in a Colony of “Hyper-responsive” Sprague Dawley Rats
Introduction: Our lab has identified a sub-strain of Sprague Dawley (SD) rats from Charles River Labs, obtained from a specific colony housed at a Canadian facility (Sherbrooke, Quebec), which develop severe progressive PAH in response to single injection of SU5416 (SU), a VEGFR2 antagonist, even in absence of chronic hypoxia (CH). This trait appears to due to the presence of unique genetic modifiers found only in this colony. Interestingly, there was a strong sex difference with >70% of males and only <30% of females showing the SU hyper-responsive (HR) phenotype. The purpose of the project was to explore the mechanisms contributing to sex related differences in response to SU alone in a hyper-responsive sub-strain of SD rats.
Hypothesis: Sex dependent differences in the HR phenotype are due to the protective effects of female sex hormones, reducing the susceptibility to PAH in response to VEGFR2 inhibition.
Methods and Results: Male and female rats were injected with SU (20mg/kg, sc) or vehicle. Right ventricular systolic pressure (RVSP) was measured at four and seven weeks after SU injection. In male SD rats, 72% (13 of 18) of rats exhibited an HR phenotype in response to SU with mean RVSP of 97±18 mmHg in absence of CH; whereas only 27% (7 of 26) of the female rats were responsive to SU alone. We studied the SU responsiveness in the oophorectomized female rats to investigate the role of female sex hormones in the sex-specific HR phenotype. Interestingly, the proportion of HR animals increased drastically in oophorectomized female rats to 71% (10 of 14), compared to non-operated female rats (33%, 4 of 12). Moreover, estradiol replacement completely abrogated the HR phenotype in both male rats and oophorectomized female rats.
Conclusion: These data support a role of female sex hormones in modulating the development of severe PAH in response to SU alone in a unique colony of SD rats that exhibit increased sensitivity to VEGFR2 blockade. The HR SD rat colony model exhibits exquisite sensitivity to estrogen and thus provides a unique opportunity to further define the complex interactions between hormonal and genetic modifiers in the development of PAH.
- Pulmonary arterial hypertension
- Sex hormones
- endothelial cell apoptosis
- pulmonary circulation
- vascular diseases
Author Disclosures: K.R. Chaudhary: None. Y. Deng: None. K. Tyson: None. A. Yang: None. D.J. Stewart: None.
- © 2015 by American Heart Association, Inc.