Cytochrome P450 epoxygenase‐derived 5,6‐epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia

Abstract

AimsThe aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase‐derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV).MethodsVasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs.ResultsPharmacological inhibition of EET synthesis with MS‐PPOH, application of the EET antagonist 14,15‐EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET‐degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre‐contracted with thromboxane mimetic U46619. However, in the presence of KCl‐induced depolarization, 5,6‐EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch‐clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6‐EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential.ConclusionsThe EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6‐EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6‐EET‐induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6‐EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV‐related diseases.

CYP2J2 and EETs protect against pulmonary arterial hypertension with lung ischemia–reperfusion injury in vivo and in vitro

“…In addition, EETs, a sort of endothelium-derived hyperpolarizing factor (eEDHF), can maintain normal endothelial cell and vascular function and can relax vascular smooth muscle cells by activating Ca 2+ -sensitive K + channels [ 35 ]. However, Strielkov et al demonstrated that EETs relaxed pulmonary arteries in normoxia but constricted in anoxia [ 36 ]. In this study, CYP2J2 decreased the pulmonary artery pressure of the rat with PAH in combined with LIRI, which might be due to the vasoprotective effects of CYP2J2 and EETs on pulmonary arteries before IR, including relaxing pulmonary arteries and decreasing vascular remodeling.…”

Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

“…EETs are short-lived mediators that have gained attention as they promote vasorelaxation of systemic vessels but induce vasoconstriction of pulmonary vessels ex vivo [78] and in vivo in hypoxia in animal models [79], and thus may account for the specific vasoconstrictive effect of hypoxia in the pulmonary vasculature [24]. However, the effects of EETs may depend on the experimental setup and the presence of sensitising factors [80]. Genetical approaches to reduce EET generation significantly reduced HPV in mice [81], while enhanced EET levels by deletion of EET-degrading sEH resulted in potentiation of HPV [79], with unaltered basal pulmonary pressures.…”

Environment and exposure

“…18 In a similar line, Strielkov et al described how epoxygenase-derived epoxyeicosatrienoic acids are involved in the regulation of pulmonary vascular tone, and may thus be utilized therapeutically for treatment of hypoxic pulmonary vasoconstriction and related diseases. 19 Sleep apnoea is a pathophysiological phenomenon of rising incidences because of, for example, the obesity epidemic, demographic change and a rise in predisposing conditions, characterized by detrimental intermittent hypoxia (reviewed in Ref. 20).…”

“…Zhang et al recently showed how keratins may counteract pulmonary artery remodelling, a major pathophysiological event in the development of pulmonary artery hypertension, which, in turn, leads to progressively increased pulmonary vascular resistance and right heart dysfunction, 17 with potential implications for novel therapeutic approaches 18 . In a similar line, Strielkov et al described how epoxygenase‐derived epoxyeicosatrienoic acids are involved in the regulation of pulmonary vascular tone, and may thus be utilized therapeutically for treatment of hypoxic pulmonary vasoconstriction and related diseases 19 …”