04 February 2019 by Ievgen Strielkov

Sustained hypoxic pulmonary vasoconstriction in mouse intrapulmonary arteries is dependent on epoxyeicosatrienoic acid pathway

Under conditions of generalized alveolar hypoxia caused by a range of lung diseases or at high altitude, exaggerated sustained hypoxic pulmonary vasoconstriction (HPV) contributes to the development of pulmonary hypertension and cor pulmonale. The exact mechanisms underlying sustained HPV are not completely understood.

The aim of the present study was to investigate the role of cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in sustained HPV. Contractile responses of isolated intrapulmonary arteries (IPAs) of C57BL/6J mice were measured using wire myography. Hypoxic exposure (80 min) induced slowly developing sustained contraction in IPAs. HPV was suppressed by a CYP epoxygenase inhibitor, MS-PPOH, abolished by an EET receptor blocker, 14,15-EEZE, and significantly potentiated by TPPU, an inhibitor of the EET-degrading enzyme, soluble epoxide hydrolase. All these agents did not affect IPA tone in normoxia. Knockdown of the soluble epoxide hydrolase gene, Ephx2, in isolated IPAs using siRNA also augmented HPV compared to non-targeting control. No changes in tone of the transfected vessels were observed in normoxia. Application of exogenous EETs (5,6-, 8,9-, 11,12- and 14,15-EET) was without effect in non-preconstricted IPAs. By contrast, in vessels preconstricted with KCl, 5,6-EET, unlike other regioisomers, induced pronounced contraction. In patch-clamp experiments, hypoxia caused depolarization in isolated mouse pulmonary artery smooth muscle cells. In normoxia, at this level of depolarization 5,6-EET evoked significant inward whole-cell currents, but not at resting membrane potential. We conclude that hypoxia activates EET synthesis in IPAs. The resulting release of 5,6-EET, presumably in conjunction with hypoxia-induced depolarization in pulmonary artery smooth muscle cells, elicits vasoconstriction.

In summary, the obtained results indicate that EET pathway contributes to sustained HPV in mouse IPA.

About the author


profile picture of Ievgen Strielkov

Ievgen Strielkov

Dr.

ECCPS, Justus-Liebig University

Germany

Key Contributors

I. V. Strielkov, N. C. Krause, F. Knöpp, R.T. Schermuly, H. A. Ghofrani, N. Weissmann : Excellence Cluster Cardiopulmonary System (ECCPS), German Center for Lung Research (DZL), Justus Liebig University Giessen, Giessen, Germany


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