Our group has reported that a specific colony of Sprague Dawley (SD) rats exhibit hyper-responsive (HR) phenotype to VEGFR2 inhibitor (SU5416, SU) and develop severe pulmonary arterial hypertension (PAH) in response to single injection of SU, even in the absence of chronic hypoxia (CH). Interestingly, the HR phenotype showed strong sex dependence. Therefore, in this project we explored the role of female sex hormones in modifying the HR phenotype in the SD HR rats.
Methods and results
Male and female rats were injected with SU (20mg/kg, sc) or vehicle and right ventricular systolic pressure (RVSP) was measured after seven weeks. In response to SU alone, 72% of male rats exhibited HR phenotype, with mean RVSP of 97±18 mmHg, as compared to only 27% of the female rats. Oophorectomy (OVX) resulted in a marked increase in the HR in female rats to 71% compared to 33% in non-operated female rats. Moreover, estradiol replacement completely abrogated the HR phenotype in both male and OVX female rats. Conversely, progesterone treatment inhibited HR phenotype only in OVX female rats but not in the male SD rats.
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. SD HR rats exhibit exquisite sensitivity to estrogen and thus provide a unique opportunity to further define the complex interactions between hormonal and genetic modifiers in the development of PAH.