Profound sex differences in a sub-strain of Sprague-Dawley rats exhibiting genetically determined hyper-responsiveness to VEGFR2 inhibition causing severe pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of narrowing or loss of lung blood vessels causing high blood pressure in the lungs and the right side of the heart. This leads to enlargement of the right side of the heart, heart failure and ultimately death. While recent developments have improved the quality of life and increased the survival time, there is no cure for this devastating disease. It is also not clear what causes this disease and how it progresses. Some genetic defects have been linked to PAH but a big portion of the cases remains unexplained. Moreover, PAH affects more female than males but female patients have better survival than males. In the animal models, majority of studies have reported protective effects of estrogens against PAH. Therefore, the role of female sex hormones in PAH is not clearly understood. In the animal model of PAH, we have observed that less female rats develop this disease than male rats, may be due to protective effects of female sex hormones. Therefore, in the proposed project, we will also investigate the effects of sex hormones in PAH. In addition, we believe that the female sex hormones are protective but the periodic withdrawal of this protective signal in female makes them susceptible to developing this disease. No study has been performed yet to investigate the effects of cyclic changes in female sex hormones on PAH. We will study the effect of changes in female sex hormones on development of PAH in PAH susceptible rat strain. We will also investigate the effect of periodic changes in female sex hormones on cell derived from susceptible and non-susceptible rats. In addition, we will perform similar experiment using the PAH patient derived endothelial cells. This work will improve our understanding of PAH and could provide novel targets for developing therapies for this incurable disease.