Microbial short chain fatty acid (SCFA) metabolites lower blood pressure (BP) via endothelial G‐protein coupled receptor 41 (Gpr41)

Abstract

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 i.v. delivery of SCFAs to anesthetized mice decreases BP by activating Gpr41, which is expressed in blood vessels (PNAS 2013). Here, our aim was to identify the cellular localization of Gpr41 and to determine the role of Gpr41 in BP regulation. Using RT‐PCR (no reliable Gpr41 antibodies are available), we observed that Gpr41 is readily detected in vessels with an intact endothelium, but is absent from vessels where the endothelium has been denuded, indicating that Gpr41 is expressed in the endothelium. Previous studies have found that SCFAs dilate blood vessels ex vivo; using microvascular chambers we confirmed that both acetate and propionate dilate resistance vessels in a dose‐dependent manner, and found that this dilation is dependent on the endothelium ‐ consistent with a role for endothelial Gpr41 in mediating this response. 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 found that Gpr41 KO (n=6) have isolated systolic hypertension and elevated pulse pressures compared to wild‐type (WT, n=6) mice (Table 1); diastolic BP was not different between genotypes. In agreement with a phenotype of systolic hypertension, KO mice also exhibited elevated pulse wave velocity in vivo (Table 1), but surprisingly, no increase in ex‐vivo aorta stiffness (measured by tensile testing experiments). Chronic administration of 200mM sodium propionate (a Gpr41 ligand) and 200mM NaCl (control) did not significantly affect BP in the WT or KO, although systolic pressure trended toward an increase for both treatments and genotypes (we hypothesize that the hypertensive effect of propionate in the KO is mediated by another SCFA receptor, Olfactory receptor 78, which we have shown to mediate increases in BP upon activation). In preliminary studies, we found no changes in plasma renin when either WT or KO animals were treated with propionate; however, we did note a slight but significant increase in blood [Na+] during sodium propionate (but not NaCl) treatments in both genotypes. In sum, these studies demonstrate that endothelial Gpr41 lowers baseline BP, likely by decreasing vascular tone.Support or Funding InformationAmerican heart association, predoctoral fellowship.Hopkins Bridge funding Gpr41 KO mice exhibit systolic hypertension, elevated pulse pressure and elevated pulse wave velocity dark cycle values shown Gpr41 WT (n=6) Gpr41 KO (n=6) systolic pressure 123.7±1.2mmHg 131.7±2mmHg p < 0.05 diastolic pressure 96.8±2 mmHg 94.7±2 mmHg n.s. pulse pressure 26.8±1.6 mmHg 36.9±1.6 mmHg p < 0.05 pulse wave velocity 3.8±0.03cm/s 4.2±0.13 cm/s p < 0.01 systolic pressure on 200mM propionate 126.6±1 mmHg 133.4±2 mmHg p < 0.05 systolic pressure on 200mM NaCl 126.6±1.5 mmHg 134.6±2.8 mmHg p < 0.05