Wei_2025_Eur.J.Pharmacol__178181

OBJECTIVES: Hyperhomocysteinemia harms vascular endothelium and smooth muscle. We recently reported that homocysteine also impairs perivascular adipose tissue (PVAT) function but the mechanisms remain poorly elucidated. This study aimed to advance mechanistic understanding of hyperhomocysteinemia-induced PVAT dysfunction through revealing the role of epoxyeicosatrienoic acids (EETs) in the anticontractile/vasorelaxing activity of PVAT. Further, the effect of targeting soluble epoxide hydrolase (sEH) against hyperhomocysteinemia-induced PVAT dysfunction was explored. METHODS: Methionine diet-induced hyperhomocysteinemic rat model and in vitro homocysteine-incubation model were used. PVAT and endothelium-intact (PVAT+E+) or both denuded (PVAT-E-), either PVAT (PVAT-E+) or endothelium-denuded (PVAT+E-) aortic rings were studied for vasoreactivity. Aortic PVAT was measured for EETs, sEH expression and activity, and transferred to skeletonized aorta for vasoreactivity regulation study. RESULTS: Both in vivo and in vitro studies showed that homocysteine augments vasocontractile responses to phenylephrine and KCl and attenuates vasorelaxant response to acetylcholine in PVAT-intact rat aortas with or without endothelium. EETs in the aortic PVAT were decreased in hyperhomocysteinemic rats (8,9-, 11,12-, 14,15-EET) and after homocysteine-exposure (11,12- , 14,15-EET), associating with an increased expression and activity of sEH. Treating in vivo and in vitro models with sEH inhibitor TPPU suppressed sEH activity and increased EETs in the PVAT, accompanied by a restored anticontractile/vasorelaxing capacity of PVAT. PVAT from TPPU-treated hyperhomocysteinemic rat suppressed the contractility of hyperhomocysteinemic rat aorta. Both 11,12- and 14,15-EET evoked relaxation in PVAT-E- aorta. CONCLUSIONS: EETs are PVAT-derived relaxing factors. Inhibition of sEH prevents homocysteine-induced EETs loss in PVAT, thereby improving the anticontractile/vasorelaxing activity of PVAT.