| First Author | Pulakazhi Venu VK | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 317 |
| Issue | 2 | Pages | E350-E361 |
| PubMed ID | 31211619 | Mgi Jnum | J:281644 |
| Mgi Id | MGI:6357350 | Doi | 10.1152/ajpendo.00572.2018 |
| Citation | Pulakazhi Venu VK, et al. (2019) The pregnane X receptor and its microbiota-derived ligand indole 3-propionic acid regulate endothelium-dependent vasodilation. Am J Physiol Endocrinol Metab 317(2):E350-E361 |
| abstractText | We proposed that circulating metabolites generated by the intestinal microbiota can affect vascular function. One such metabolite, indole 3-propionic acid (IPA), can activate the pregnane X receptor(PXR), a xenobiotic-activated nuclear receptor present in many tissues, including the vascular endothelium. We hypothesized that IPA could regulate vascular function by modulating PXR activity. To test this, Pxr(+/+) mice were administered broad-spectrum antibiotics for 2 wk with IPA supplementation. Vascular function was evaluated by bioassay using aorta and pulmonary artery ring tissue from antibiotic-treated Pxr(+/+) and Pxr(-/-)mice, supplemented with IPA, and using aorta tissue maintained in organ culture for 24 h in the presence of IPA. Endothelium-dependent, nitric oxide(NO)-mediated muscarinic and proteinase-activated receptor 2(PAR2)-stimulated vasodilation was assessed. Endothelial nitric oxide synthase (eNOS) abundance was evaluated in intact tissue or in aorta-derived endothelial cell cultures from Pxr(+/+) and Pxr(-/-) mice, and vascular Pxr levels were assessed in tissues obtained from Pxr(+/+) mice treated with antibiotics and supplemented with IPA. Antibiotic-treated Pxr(+/+) mice exhibited enhanced agonist-induced endothelium-dependent vasodilation, which was phenocopied by tissues from either Pxr(-/-) or germ-free mice. IPA exposure reduced the vasodilatory responses in isolated and cultured vessels. No effects of IPA were observed for tissues obtained from Pxr(-/-) mice. Serum nitrate levels were increased in antibiotic-treated Pxr(+/+)and Pxr(-/-) mice. eNOS abundance was increased in aorta tissues and cultured endothelium from Pxr(-/-) mice. PXR stimulation reduced eNOS expression in cultured endothelial cells from Pxr(+/+) but not Pxr(-/-) mice. The microbial metabolite IPA, via the PXR, plays a key role in regulating endothelial function. Furthermore, antibiotic treatment changes PXR-mediated vascular endothelial responsiveness by upregulating eNOS. |
