Natarajan Niranjana, Hori Daijiro, Flavahan Sheila, Steppan Jochen, Flavahan Nicholas A, Berkowitz Dan E, Pluznick Jennifer L
Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland; and.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
Physiol Genomics. 2016 Nov 1;48(11):826-834. doi: 10.1152/physiolgenomics.00089.2016. Epub 2016 Sep 23.
Short chain fatty acid (SCFA) metabolites are byproducts of gut microbial metabolism that are known to affect host physiology via host G protein-coupled receptor (GPCRs). We previously showed that an acute SCFA bolus decreases blood pressure (BP) in anesthetized mice, an effect mediated primarily via Gpr41. In this study, our aims were to identify the cellular localization of Gpr41 and to determine its role in BP regulation. We localized Gpr41 to the vascular endothelium using RT-PCR: Gpr41 is detected in intact vessels (with endothelium) but is absent from denuded vessels (without endothelium). Furthermore, using pressure myography we confirmed that SCFAs dilate resistance vessels in an endothelium-dependent manner. Since we previously found that Gpr41 mediates a hypotensive response to acute SCFA administration, we hypothesized that Gpr41 knockout (KO) mice would be hypertensive. Here, we report that Gpr41 KO mice have isolated systolic hypertension compared with wild-type (WT) mice; diastolic BP was not different between WT and KO. Older Gpr41 KO mice also exhibited elevated pulse wave velocity, consistent with a phenotype of systolic hypertension; however, there was no increase in ex vivo aorta stiffness (measured by mechanical tensile testing). Plasma renin concentrations were also similar in KO and WT mice. The systolic hypertension in Gpr41 KO is not salt sensitive, as it is not significantly altered on either a high- or low-salt diet. In sum, these studies suggest that endothelial Gpr41 lowers baseline BP, likely by decreasing active vascular tone without altering passive characteristics of the blood vessels, and that Gpr41 KO mice have hypertension of a vascular origin.
短链脂肪酸（SCFA）代谢产物是肠道微生物代谢的副产物，已知其通过宿主G蛋白偶联受体（GPCR）影响宿主生理功能。我们之前发现，急性给予SCFA团注可降低麻醉小鼠的血压（BP），这一效应主要通过Gpr41介导。在本研究中，我们的目的是确定Gpr41的细胞定位，并确定其在血压调节中的作用。我们使用逆转录聚合酶链反应（RT-PCR）将Gpr41定位到血管内皮：在完整血管（有内皮）中检测到Gpr41，但在去内皮血管（无内皮）中未检测到。此外，使用压力肌动描记法，我们证实SCFAs以内皮依赖的方式扩张阻力血管。由于我们之前发现Gpr41介导对急性给予SCFA的降压反应，我们推测Gpr41基因敲除（KO）小鼠会出现高血压。在此，我们报告Gpr41 KO小鼠与野生型（WT）小鼠相比存在孤立性收缩期高血压；WT和KO小鼠的舒张压无差异。老年Gpr41 KO小鼠还表现出脉搏波速度升高，与收缩期高血压的表型一致；然而，离体主动脉僵硬度（通过机械拉伸试验测量）没有增加。KO和WT小鼠的血浆肾素浓度也相似。Gpr41 KO小鼠的收缩期高血压对盐不敏感，因为在高盐或低盐饮食下其血压均无显著变化。总之，这些研究表明，内皮Gpr41可能通过降低主动血管张力而不改变血管的被动特性来降低基线血压，并且Gpr41 KO小鼠患有血管源性高血压。
