High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

Abstract

This study aims to investigate the signaling mechanism involved in HS-induced modulation of adenosine-mediated vascular tone in the presence or absence of adenosine A2A receptor (A2AAR). We hypothesized that HS-induced enhanced vascular relaxation through A2AAR and epoxyeicosatrienoic acid (EETs) is dependent on peroxisome proliferator-activated receptor gamma (PPARγ) and ATP-sensitive potassium channels (KATP channels) in A2AAR+/+ mice, while HS-induced vascular contraction to adenosine is dependent on soluble epoxide hydrolase (sEH) that degrades EETs in A2AAR−/− mice. Organ bath and Western blot techniques were conducted in HS (4 % NaCl) and normal salt (NS, 0.45 % NaCl)-fed A2AAR+/+ and A2AAR−/− mouse aorta. We found that enhanced vasodilation to A2AAR agonist, CGS 21680, in HS-fed A2AAR+/+ mice was blocked by PPARγ antagonist (T0070907) and KATP channel blocker (Glibenclamide). Also, sEH inhibitor (AUDA)-dependent vascular relaxation was mitigated by PPARγ antagonist. PPARγ agonist (Rosiglitazone)-induced relaxation in HS-A2AAR+/+ mice was attenuated by KATP channel blocker. Conversely, HS-induced contraction in A2AAR−/− mice was attenuated by sEH inhibitor. Overall, findings from this study that implicates the contribution of EETs, PPARγ and KATP channels downstream of A2AAR to mediate enhanced vascular relaxation in response to HS diet while, role of sEH in mediating vascular contraction in HS-fed A2aAR−/− mice.

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

“…Additionally, sEH inhibition reduced A 1 AR-dependent aortic contractions in A 2A AR −/− mice [21]. These findings strongly suggested a potential role for sEH in regulating A 1 AR-dependent vascular function.…”

“…Various studies revealed that a decrease in A 1 AR levels closely followed a decrease in sEH expression, and vice versa in sEH −/− and A 2A AR −/− mouse aortas [19, 21]. Additionally, sEH inhibition reduced A 1 AR-dependent aortic contractions in A 2A AR −/− mice [21].…”

“…In A 2A AR −/− mouse aorta, we found higher expression of A 1 AR [20] and sEH [21]. Moreover, in mouse aorta of A 2A AR −/− , sEH inhibition significantly reduced A 1 AR-induced vascular contraction [21]. These findings strongly indicate a relationship between sEH and ARs, especially A 1 AR, which plays an important role in the regulation of vascular tone.…”

“…This increase in relaxation was attributed to enhanced A 2A AR and decreased A 1 AR protein expression [19]. In A 2A AR −/− mouse aorta, we found higher expression of A 1 AR [20] and sEH [21]. Moreover, in mouse aorta of A 2A AR −/− , sEH inhibition significantly reduced A 1 AR-induced vascular contraction [21].…”

“…In mouse MAs, K ATP channels were involved in A 2B AR-dependent vascular relaxation [26]. Notably, in wild type (WT) mice, sEH inhibition resulted in enhanced A 2A AR-dependent aortic relaxation [21]. Thus, sEH may regulate K ATP channel-dependent vascular relaxation, which involves A 1 AR, CYP4A, ERK1/2, and PKCα.…”