Previously, we showed vascular endothelial overexpression of human-CYP2J2 enhances coronary reactive hyperemia in Tie2-CYP2J2 Tr mice, and eNOS −/− mice had overexpression of CYP2J-epoxygenase with adenosine A 2A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5-gene deletion affects acetylcholine-and 5'-Nethylcarboxamidoadenosine (NECA) (adenosine)-induced relaxation and their response is partially inhibited by angiotensin-II (Ang-II) in mice. Acetylcholine (Ach)-induced response was tested with N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10 −5 M) and Ang-II (10 −6 M). In Cyp2j5 −/− mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10 −5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in Cyp2j5 −/− : 58.5 ± 5.0%, P > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P < 0.05, and Ang-II reduces AChinduced relaxation in both Cyp2j5 −/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P <0.05). In addition, NECA-induced response was tested with Ang-II. In Cyp2j5 −/− mice, NECA-induced response was not different from C57Bl/6 mice at 10 −5 M (23.1 ± 2.1 vs. 21.1 ± 3.8, P > 0.05). However, NECA-induced response was reduced by Ang-II in both Cyp2j5 −/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P < 0.05). Data suggest that ACh-induced relaxation in Cyp2j5 −/− mice depends on nitric oxide (NO) but not CYPepoxygenases, and the NECA-induced different response in male vs. female Cyp2j5 −/− mice when Ang-II treated.

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Previously, we have reported that the coronary reactive hyperemic response was reduced in adenosine A 2A receptor-null (A 2A AR −/− ) mice, and it was reversed by the soluble epoxide hydrolase (sEH) inhibitor. However, it is unknown in aortic vascular response, therefore, we hypothesized that A 2A AR-gene deletion in mice (A 2A AR −/−

Previously, we showed vascular endothelial overexpression of human‐CYP2J2 enhances coronary reactive hyperemia in Tie2‐CYP2J2 Tr mice, but we did not see the response in CYP2J‐epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5‐gene deletion affects acetylcholine‐, NECA (adenosine)‐and CGS 21680 (adenosine A2A receptor)‐induced relaxation and their response is partially inhibited by angiotensin‐II (Ang‐II) and ω‐hydroxylase inhibitor in mice. ACh‐induced response was tested with N‐(methylsulfonyl)‐2‐(2‐propynyloxy)‐benzenehexanamide (MS‐PPOH, CYP‐epoxygenase inhibitor; 10–5M) and Ang‐II (10‐6M). In Cyp2j5−/− mice, ACh‐induced relaxation was different from C57Bl/6 mice, at 10‐5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P<0.05). However, ACh‐induced relaxation was not blocked by MS‐PPOH in Cyp2j5−/−: 58.5 ± 5.0%, P>0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P<0.05, and Ang‐II reduces ACh‐induced relaxation in both Cyp2j5−/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P <0.05). In addition, NECA‐induced response tested with Ang‐II and 20‐HETE inhibitor, dibromo‐dodecenyl‐methylsulfimide (DDMS, 10‐5M). In Cyp2j5−/− mice, NECA‐induced response was not different from C57Bl/6 mice at 10‐5M (23.1 ± 2.1 vs. 21.1 ± 3.8, P>0.05). However, NECA‐induced response was reduced by Ang‐II in both Cyp2j5−/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P <0.05), and the reduced response due to Ang‐II was partially rescued by DDMS in both Cyp2j5−/− and C57Bl/6 mice (at 10‐5M, A2AAR‐agonist, CGS‐21680, 15.8 ± 3.4% and 13.0 ± 2.3, P <0.05). Data suggest that ACh‐induced relaxation in Cyp2j5−/− mice depends on nitric oxide (NO) but not CYP‐epoxygenases, and the NECA‐induced different response in male vs. female Cyp2j5−/− mice when Ang‐II treated. Support or Funding Information National Institutes of Health (HL‐114559) to M. A. Nayeem and the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01 ES025034) to D. C. Zeldin supported this work. Flow diagram: Comparison between Cyp2j5−/− vs. C57Bl/6 mice treated with Acetylcholine, Acetylcholine + MS‐PPOH, Acetylcholine + Ang‐II, NECA, NECA + Ang‐II and CGS 21680 + DDMS + Ang‐II.

Previously, we reported that the coronary reactive hyperemic response (CRH) was reduced in adenosine A2A receptor‐null (A2AAR‐/‐) mice, and reversed by soluble epoxide hydrolase (sEH) inhibitor. However, this is unknown in aortic vascular response; therefore, we hypothesized that A2AAR‐gene deletion in mice (A2AAR‐/‐) affects adenosine‐induced vascular response by increasing sEH and adenosine A1 receptor (A1AR) activities. A2AAR‐/‐ mice showed an increase in sEH, AI AR and CYP450‐4A protein expression but decrease in CYP450‐2C compared to C57Bl/6 mice. NECA (adenosine‐analog) and CCPA (adenosine A1 receptor‐agonist)‐induced dose‐dependent vascular response was tested with t‐AUCB (sEH‐inhibitor) and angiotensin‐II (Ang‐II) in A2AAR‐/‐ vs. C57Bl/6 mice. In A2AAR‐/‐, NECA and CCPA‐induced increase in dose‐dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA‐induced dose‐dependent vascular contraction in A2AAR‐/‐ was reduced by t‐AUCB with NECA. Similarly, dose‐dependent vascular contraction in A2AAR‐/‐ was reduced by t‐AUCB with CCPA. In addition, Ang‐II enhanced NECA and CCPA‐induced dose‐dependent vascular contraction in A2AAR‐/‐ with NECA. Similarly, the dose‐dependent vascular contraction in A2AAR‐/‐ was also enhanced by Ang‐II with CCPA. Furthermore, t‐AUCB reduced Ang‐II‐enhanced NECA and CCPA‐induced dose‐dependent vascular contraction in A2AAR‐/‐mice. Our data suggest that the dose‐dependent vascular contraction in A2AAR‐/‐ mice depends on increase in sEH, A1AR and CYP4A protein expression.