EET‐dependent Potentiation of Pulmonary Arterial Pressure: A Role of Sex Differences

Aim To study the effect of epoxyeicosatrienoic acids (EETs) on sex‐specific control of pulmonary arterial pressure. Methods: Male and female Wild type (WT) and soluble epoxide hydrolase knockout (sEH‐KO) mice were anesthetized. Right ventricular systolic pressure (RVSP) and systemic arterial blood pressures (MABP) were continuously recorded in response to U46619 (0.01‐0.2 nm/kg) and 14,15‐EET (1–10ug/kg). Results: In control conditions, MABP was significantly lower in both sexes of sEH‐KO mice compared to their WT controls. In male mice, intravenous administration of U46619 initiated dose‐dependent increases in RVSP and MABP. However, the increase in RVSP was significantly greater in sEH‐KO mice, associated with a smaller increase in MABP, compared to WT controls. These results suggest that sEH‐KO‐induced high vascular EETs promote U46619‐induced constriction in pulmonary circulation but antagonize the hypertensive response in systemic circulation. In female sEH‐KO mice, U46619‐induced increases in RVSP were even higher than male sEH‐KO and female WT mice. Administration of 14,15‐EET produced dose‐dependent increases in RVSP in all groups of mice. The increase was significantly greater in both sexes of sEH‐KO mice than their WT controls. The potentiated U46619‐ and EET‐induced increase in RVSP in female sEH‐KO mice were prevented by 14,15‐EEZE (an antagonist of EETs). Conclusions 1) 14,15‐EET initiates vasoconstriction in the pulmonary vasculature, but vasodilation in the systemic circulation; 2) high vascular EETs potentiate U46619‐induced increases in RVSP; 3) there is a female phenotype‐dependent promotion of increases in RVSP in sEH‐KO mice. (This work was supported by NIH HL070653 and HL115124)