PROJECT ABSTRACT The role of sex in cardiovascular disease (CVD) remains a critically understudied area in determining the etiology, pathology, and effective treatments. Whereas men experience a gradual increase in CVD risk over the lifespan, premenopausal women are protected from CVD-related pathologies. However, post-menopause the onset of CVD in women increases dramatically. Endothelial cell dysfunction may contribute to these sex and sex hormone-dependent differences in CVD risk. Here we seek to investigate the impact of sex and sex hormone- dependent differences in progression of the CVD disease pulmonary hypertension secondary to left heart failure (PH-LHF). Aim 1: Investigate the role of sex and sex hormones in pulmonary endothelial cell mechanotransduction and disease progression. First, we will test the hypothesis that female sex alters endothelial cell signaling in response to mechanical shear stress. Human male and female pulmonary artery, vein, and microvascular endothelial cells will be exposed to physiologic, high, and low levels of shear stress (σ) to measure the effect of sex independent of sex hormones. Second, to investigate the role of sex coupled with female sex hormones, both male and female cells will be dosed with sex hormones at physiologic or pathologic σ. These in vitro results will be confirmed as drivers of collagen over-production and chronic vasoconstriction in vivo using the established mouse model of PH-LHF. Aim 2: Determine the role of sex and sex hormones in the progression of PH-LHF with a coupled pulmonary hemodynamics and endothelial cell kinetics model of PH-LHF. Informed by the existing literature, we will develop a chemical kinetics model of the endothelial response to altered σ, sex, and sex hormones. Using idealized human structural and hemodynamic data we will develop a computational model of the pulmonary vasculature integrated with the chemical kinetics equations for key signaling factors. Parameter values and dependencies will be validated against the in vitro data collected in Aim 1. To confirm predictive capability, the model will be calibrated to the in vivo mouse model of PH-LHF and used to estimated pulmonary artery and vein remodeling.

PROJECT NARRATIVE Left heart failure (LHF) frequently leads to pulmonary hypertension (PH) and right ventricular failure. Whereas sex differences in the rare and rapidly fatal disease pulmonary arterial hypertension (PAH) are known, it is unclear whether sex- and sex hormone-dependent differences exist in PH due to LHF. Our goal is to advance knowledge of molecular and mechanical mechanisms of progression of PH due to LHF with a focus on sex differences.