Sexual dimorphism in right (-sided) heart failure: Role of sphingosine kinsae-1 and progesterone in right ventricular angiogenesis and remodelling

The right ventricle (RV) of the heart normally functions against low pressure and resistance. However, in patients with increased blood pressure in the lungs (pulmonary hypertension), the RV is exposed to higher pressure and resistance that leads to increased RV wall thickness and ultimately right heart failure (RHF, inability of the RV to pump blood) and death. Recent studies have shown that patients with stable RV function have better survival than patients whose RV function is deteriorating. Therefore, treatments that can prevent deterioration of RV function can improve survival of these patients. Unfortunately, there is no specific therapy available targeting the RV. Therefore, there is a need for better understanding of processes involved in RHF for development of new RV specific therapies. Importantly, females have better RV function under normal condition as well as in response to increased pressure compared to males; however, the mechanisms remain unknown. Our research focuses on understanding these important differences to design new therapies and better treatment for RHF. Our preliminary data, using animal models, showed better RV structure and function in female rats compared to male rats. This effect was associated with higher expression of genes linked to blood vessel growth in the female RV including sphingosine kinase-1 (Sphk1). Interestingly, progesterone, a major female sex hormone, promotes blood vessel formation by Sphk1. Therefore, in this project, we will investigate how progesterone and Sphk1 affects blood vessel growth in the RV and if that is the cause for male-female differences in RHF. Importantly, subjects with lower progesterone levels have poor RV function. Therefore, findings from these studies will be relevant to patients with low progesterone such as males, and females affected by polycystic ovary syndrome and menopause. The knowledge acquired from this project will form the base for development of specific therapy for RHF.