Sex Differences in Immunology: More Severe Development of Experimental Pulmonary Hypertension in Male Rats Exposed to Vascular Endothelial Growth Factor Receptor Blockade

BACKGROUND: The epidemiology of pulmonary hypertension (PH) is characterized by a female preponderance, whereas males share higher severity of the disease.

OBJECTIVE: To compare the severity of experimental PH between male and female athymic rats.

METHODS: PH was induced in 11 male and 11 female athymic rats (resp., SU_M and SU_F groups) using an inhibitor of VEGF-receptors I and II, semaxanib (40 mg/kg). After 28 days, right ventricular (RV) remodeling, systolic function, and hemodynamics were measured using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV myocardium were performed.

RESULTS: Four weeks after semaxanib injection, RV end-systolic pressure was higher in SU_M than in SU_F. Males developed marked RV enlargement and systolic dysfunction compared to females. Impairment of RV-PA coupling efficiency was observed only in SU_M. The smooth muscle cells of the pulmonary arteries switched from a contractile state to a dedifferentiated state only in males.

CONCLUSIONS: Female athymic rats were protected against the development of severe PH. RV-PA coupling was preserved in females through limitation of pulmonary artery muscularization. Control of smooth muscle cells plasticity may be a promising therapeutic approach to reverse established vascular remodeling in PH patients.