Abstract 030: Microbial Short Chain Fatty Acid (SCFA) Metabolites Lower Blood Pressure (BP) via Endothelial G-protein Coupled Receptor 41 (gpr41)

Abstract

Short chain fatty acid (SCFA) metabolites (acetate, propionate and butyrate) are byproducts of gut microbial metabolism that affect host physiology, and have been shown to dilate blood vessels ex vivo . We have previously shown that intravenous delivery of SCFAs to anesthetized mice decreases BP by activating Gpr41, which is expressed in blood vessels. Here, our aim was to identify the cellular localization of Gpr41 and to determine the role of Gpr41 in BP regulation. Using RT-PCR we observe that Gpr41 is readily detected in vessels with an intact endothelium, but is absent from vessels where the endothelium has been denuded. Thus Gpr41 is expressed in the endothelium. Since Gpr41 was previously found to mediate a hypotensive response to acute SCFA administration, we hypothesized that Gpr41 knockout (KO) mice would be hypertensive at baseline. Concordant with our hypothesis, we find that Gpr41 KO (n=4) have elevated systolic hypertension and pulse pressures compared to wild-type (WT, n=4) mice (Table 1); diastolic BP was not different between genotypes. In agreement with a phenotype of systolic hypertension, KO mice also exhibit elevated pulse wave velocity (Table 1). Administration of 200mM sodium propionate (a Gpr41 ligand) in the drinking water worsens the systolic hypertension in KO (Table 1), while administration of equimolar sodium chloride (control) does not affect BP in WT or KO. We hypothesize that the hypertensive effect of propionate in KO is mediated by another SCFA receptor, Olfactory receptor 78 (which we have previously shown to mediate increases in BP upon activation). In sum, these studies demonstrate that endothelial Gpr41 acts to lower baseline BP.