EET‐dependent attenuation of coronary myogenic constriction in response to deletion/downregulation of soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) catabolizes epoxyeicosatrienoic acids (EETs) to form DHETs that lack, or have less, cardioprotective properties. Thus, we hypothesized that a sex‐different regulation of pressure‐induced myogenic constriction in coronary arteries involves sEH‐dependent signaling. Pressure‐diameter relationships were assessed in isolated and cannulated coronary arteries of male (M) and female (F) wild type (WT) and sEH‐knockout (KO) mice. All vessels constricted in response to increases in intraluminal pressure from 60 to 120 mmHg. Myogenic constriction was significantly attenuated, associated with higher cardiac EETs and lower DHETs in M‐KO, F‐WT and F‐KO mice compared to M‐WT controls. Blockade of EETs with 14,15‐EEZE prevented the attenuated myogenic constriction in sEH‐KO mice. In the presence of EEZE, pressure‐diameter curves of females presented an upward‐shift from those of males, manifesting a sex‐different phenotype. Additional administration of L‐NAME eliminated the sex‐difference, leading to four overlapped pressure‐diameter curves. Cardiac sEH was downregulated in F‐WT compared to M‐WT mice, whereas the expression of eNOS was comparable among the groups. In summary, in combination with NO, the increased EET bioavailability as a function of genetic deletion and/or downregulation of sEH accounts for the female‐favorable attenuation of pressure‐induced constriction. Support or Funding Information This work was supported by grant NIH HL070653 and HL34300