TY  - JOUR
A1  - Malacarne, Pedro Felipe
A1  - Bezzenberger, Justus
A1  - López Sciarra, Melina
A1  - Warwick, Timothy
A1  - Müller, Niklas
A1  - Brandes, Ralf
A1  - Rezende Felipe, Flávia Figueiredo de
T1  - Epoxyeicosatrienoic acid and prostanoid crosstalk at the receptor and intracellular signaling levels to maintain vascular tone
T2  - International journal of molecular sciences
N2  - Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) for their activity. We set out to determine the contribution of endothelial CYP450 to murine vascular function using isolated aortic ring preparations from tamoxifen-inducible endothelial cell-specific POR knockout mice (ecPOR−/−). Constrictor responses to phenylephrine were similar between control (CTR) and ecPOR−/− mice. Contrastingly, sensitivity to the thromboxane receptor agonist U46619 and prostaglandin E2 (PGE2) was increased following the deletion of POR. Ex vivo incubation with a non-hydrolyzable EET (14,15-EE-8(Z)-E, EEZE) reversed the increased sensitivity to U46619 to the levels of CTR. EETs had no effect on vascular tone in phenylephrine-preconstricted vessels, but dilated vessels contracted with U46619 or PGE2. As U46619 acts through RhoA-dependent kinase, this system was analyzed. The deletion of POR affected the expression of genes in this pathway and the inhibition of Rho-GTPase with SAR407899 decreased sensitivity to U46619. These data suggest that EET and prostanoid crosstalk at the receptor level and that lack of EET production sensitizes vessels to vasoconstriction via the induction of the Rho kinase system.
KW  - epoxyeicosatrienoic acid
KW  - nitric oxide
KW  - thromboxane
KW  - prostaglandins
KW  - arachidonic acid
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77666
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-776666
SN  - 1422-0067
N1  - The study was supported by the Deutsche Forschungsgemeinschaft (RE 4360/2-1 to FR; SFB834/3 TP A2 to RPB and SFB1039 to RPB, Excellent Cluster Cardio-Pulmonary Institute EXS2026), the Medicine Faculty of the Goethe University (Frankfurt, Germany); the German Center for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt; as well as the Dr. Rolf-Schwiete Stiftung.
VL  - 23
IS  - 11, art. 5939
SP  - 1
EP  - 12
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -