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

Abstract

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)