NYMC Faculty Publications

EETs Promote Hypoxic Pulmonary Vasoconstriction Via Constrictor Prostanoids

DOI

10.1152/ajplung.00038.2017

Journal Title

American Journal of Physiology.Lung Cellular and Molecular Physiology

First Page

L350

Last Page

L359

Document Type

Article

Publication Date

8-1-2017

Department

Physiology

Abstract

To test the hypothesis that epoxyeicosatrienoic acids (EETs) facilitate pulmonary responses to hypoxia, male wild type (WT) and soluble epoxide hydrolase knockout (sEH-KO) mice, and WT mice chronically fed a sEH inhibitor (t-TUCB; 1mg/kg/day) were used. Right ventricular systolic pressure (RVSP) was recorded under control and hypoxic conditions. The control RVSP was comparable among all groups. However, hypoxia elicited increases in RVSP in all groups with predominance in sEH-KO and t-TUCB-treated mice. 14,15-EEZE (EET antagonist) attenuated the hypoxia-induced greater elevation of RVSP in sEH-deficient mice, suggesting an EET-mediated increment. Exogenous 5,6-; 8,9- or 14,15-EET (0.05ng/gram body weight) did not change RVSP in any conditions, but 11,12-EET enhanced RVSP under hypoxia. Isometric tension was recorded from pulmonary arteries isolated from WT and sEH-KO mice, vessels that behaved identically in their responsiveness to vasoactive agents and vessel stretch. Hypoxic pulmonary vasoconstriction (HPV, expressed as increases in hypoxic force) was significantly greater in vessels of sEH-KO than WT vessels; the enhanced component was inhibited by EEZE. Treatment of WT vessels with 11,12-EET enhanced HPV to the same level as sEH-KO vessels, confirming EETs as primary players. Inhibition of cyclooxygenases (COXs) significantly enhanced HPV in WT vessels, but attenuated HPV in sEH-KO vessels. Blocking/inhibiting COX-1, prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptors and TXA synthase prevented the enhanced HPV in sEH-KO vessels, but had no effects on WT vessels. In conclusion, an EET-dependent alteration in PG-metabolism that favors the action of vasoconstrictor PGH2 and TXA2 potentiates HPV and hypoxia-induced elevation of RVSP in sEH-deficient mice.

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