Pro‐Resolving Lipid Mediators Reduce Acetylcholine‐Induced Contractions in Resistance Arteries from Hypertensive Rats

Abstract

Aims It is well known that low-grade chronic inflammation induces vascular dysfunction and contributes to hypertension. On the other hand, resolution of inflammation is an active phenomenon to switch off the inflammatory processes once the harmful stimuli is removed and facilitate the return to homeostasis. Increasing the levels of pro-resolving mediators to promote the resolution of inflammation is emerging as a novel therapeutic approach. Arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid produce pro-resolving lipid mediators lipoxin A4 (LXA4), resolvin D1 (RvD1), and resolvin E1 (RvE1), respectively, through the 5-lipoxygenase enzymatic pathway. However, it is unknown if pro-resolving lipid mediators can ameliorate dysfunction in arteries from hypertensive animals. Therefore, we hypothesized that pro-resolving lipid mediators decrease acetylcholine-induced contractions in arteries from spontaneously hypertensive rats (SHR). Methods Mesenteric resistance arteries (MRA) (lumen diameter ~ 250 µm) from male SHR and Wistar Kyoto (WKY) (14-weeks old, n=3) were collected to assess vascular function via wire myograph. After testing vascular smooth muscle cell integrity, MRA were incubated with either RvD1, RvE1, or LXA4 (10 nM, 1 hour) or vehicle prior to concentration response curves to acetylcholine (1 nM - 3 µM). Phenylephrine (10 µM) was used to contract the arteries prior relaxation curves. Results As expected, low concentrations (≤ 100 nM) of acetylcholine induced relaxation in arteries from both groups, however high concentrations (≥ 1 µM) of acetylcholine induced contraction in arteries from SHR, but not in WKY [Maximum response (Emax): WKY: 94.5 ± 3.3 vs. SHR-control: 44.9 ± 12.5* %, t-test *vs. WKY, p=0.01). Treatment with the pro-resolving lipid mediators did not change acetylcholine-induced relaxation in arteries from WKY (Vehicle: 94.5 ±3.3 vs. RvD1: 95.8 ± 0.8; RvE1: 90.1 ± 7.1; LXA4: 93.5 ± 3.9 %, p>0.05). However, incubation with RvE1 abolished acetylcholine induced-contraction in arteries from SHR and promoted relaxation (Vehicle: 44.9 ± 12.5 vs. RvE1: 94.1 ± 3.5%,* t-test *vs. vehicle, p<0.05). While acetylcholine-induced contraction abolishment from incubation with RvD1 and LXA4 did not reach significance due to small sample size in arteries from SHR, we did observe a tendency towards improvement. Conclusion Overall, these results suggest that pro-resolving lipid mediators biosynthesized from the 5-lipoxygenase enzymatic pathway improved endothelium-dependent relaxation in arteries from hypertensive animals. As docosahexaenoic acid and eicosapentaenoic acid are already recommended to protect against many cardiovascular diseases, our work suggests that RvD1, RvE1, or LXA4 may also be used as a new therapeutic tool to specifically improve vascular function in hypertension.