Precursors of specialized pro-resolving mediators (SPMs) are decreased in hypertension, and treatment with SPMs improve vascular relaxation via formyl peptide-receptor-2

Abstract

Specialized pro-resolving mediators (SPMs), derived from essential fatty acids, play an immunoregulatory role. Formyl peptide receptor-1 is a pattern recognition receptor that mediate host-defense and inflammation. On the other hand, FPR2 binds SPMs to induce resolution of inflammation. It is well known that low-grade chronic inflammation is present in hypertension, but it is unknown whether this phenomenon occurs due to dysregulation of resolution of inflammation. Also, it is unclear if arteries can sense SPM. We hypothesized that the resolution of inflammation is decreased in hypertension, and treatment with SPM will improve vascular function via FPR-2. Forty-five eicosanoids, precursors of SPMs were detected in the plasma of male Wistar Kyoto rats (WKY) (14 weeks old, n=10) and spontaneously hypertensive rats (SHR; 14 weeks old, n=16). Analysis revealed a significant decrease (%) in 5 different eicosanoids in SHR (1) free eicosapentaenoic acid (60%), (2) free adrenic acid (25%), (3) 20-carboxy-arachidonic acid (52%) (4) 5-hydroxyeicosatetraenoic acid (20%), and (5) 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) (48%). Additionally, mesenteric resistance arteries (MRA, lumen diameter < 300 μm) from SHR rats showed significant oxidative degradation of lipids measured by the presence of 4-hydroxynonenal (4-HNE) (4-HNE; AU: WKY: 3.8±0.6 vs. SHR: 14.4±3.8; p=0.02). MRA were mounted in a wire myograph to evaluate vascular function, and concentration-response curves (CRC) to acetylcholine (ACh 10−9 to 10−5 mol/L) were performed. As expected, relaxation was impaired in MRA from SHR compared to WKY. This was noted by a shift to the right in the CRC, increasing (%) area under the curve (ΔAUC: 20± 4%). On the other hand, SPMs (10 nM) restored this response by shifting the CRC to the left and reducing the AUC compared to arteries from SHR treated with vehicle [SPMs: Resolvin D1 (RvD1) (ΔAUC:19±4%), Resolvin E1 (RvE1) (ΔAUC: 8.5 ± 9%), and lipoxin A4 (ΔAUC: 20±7%,)]. Specific antagonism of FPR-2 (WRW4, 1μM) abolished the improvement in relaxation induced by SPMs. Superoxide indicator dihydroethidium (DHE) was used in primary MRA endothelial cell culture. SPMs reduced the formation of reactive oxygen species after an inflammatory stimulus [Control: 99±2.5%; TNFα: 272± 50%; RvD1: 109±25%; RvE1: 111±22%; LXA4: 101±10%, A.U.). However, WRW4 did not change these responses. Total FPR2 and lipoxygenase 5 (LOX-5) protein expression was similar in arteries from WKY and SHR. However, there was an increase in LOX-5 serine 523 phosphorylation in SHR, suggesting a compensatory mechanism to increase local LXA4. Overall, SPMs play an important role to maintain vascular heath, and their effects occur both dependent and independent of FPR2 activation. Improvement of resolution of inflammation maybe a new treatment for for hypertension. National Institutes of Health - R00GM118885, R01HL149762, R00HL151889, and RO1DK132948. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.