Sex differences in the pulmonary microvascular endothelial responses to hypoxia under physiological shear stress

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are commonly complicated by the development of pulmonary hypertension (PH), which significantly increases the morbidity and mortality. Sexual dimorphism exists in PH. Females with PH due to lung diseases and/or hypoxia have higher pulmonary vascular resistance than males. However, females have better survival with PH than males. Recent studies suggest that sex hormone independent mechanisms contribute to the protection of males from the development of pulmonary arterial hypertension. However, it remains unknown whether sex hormone independent mechanisms contribute to the sex bias in PH due to lung diseases and/or hypoxia. Pulmonary endothelial cells play a crucial role in the pulmonary vascular remodelling and vasoconstriction in the response to hypoxia. Commonly, endothelial cell responses are studied in vitro in static conditions, i.e., without flow-induced shear stress. However, in vivo endothelial cells constantly experience shear stress, which regulates endothelial cell phenotype and function. The aim of the studies reported in this thesis was to examine the sex differences in the responses of human pulmonary microvascular endothelial cells (HPMEC) to hypoxia, cultured under physiological shear stress, that are independent of the sex hormone environment. In order to expose HPMEC to the hypoxic environment in the conditions of physiological shear stress a novel approach was established. In these conditions sex differences between male and female HPMEC were identified on the RNA and protein levels. Endothelial to mesenchymal transition was higher in female cells and proliferation rate was higher in male cells. The identified sex different pathways might contribute to the sex bias in pulmonary hypertension.