INTERPLAY OF MICROBIAL SHORT CHAIN FATTY ACIDS AND HOST G-PROTEIN COUPLED RECEPTORS IN BLOOD PRESSURE REGULATION

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dc.contributor.advisorSchramm, Lawrence
dc.contributor.committeeMemberPluznick, Jennifer L.
dc.contributor.committeeMemberGuggino, William B.
dc.contributor.committeeMemberWong, Guang William
dc.creatorNatarajan, Niranjana
dc.date.accessioned2018-05-22T03:54:50Z
dc.date.available2018-05-22T03:54:50Z
dc.date.created2016-12
dc.date.issued2016-07-25
dc.date.submittedDecember 2016
dc.date.updated2018-05-22T03:54:51Z
dc.description.abstractThe role of commensal microbiota in modulating host physiology is a rapidly emerging and expanding concept. The composition of microbiota is diverse and dynamic depending on diet and environmental factors. Changes in the composition of the microbiota have been correlated with a variety of pathophysiological processes, including cardiovascular disease and hypertension. One of the well-characterized classes of gut microbial metabolites are short chain fatty acids (SCFAs), which are produced by the breakdown of dietary fiber in the colon. Recent studies have found that SCFAs produced by the gut microbiota modulate host physiology by acting as ligands for host G-protein coupled receptors (GPCRs), including Gpr41, Gpr43 and Olfr78. Gpr41, also referred to as Ffar3, is a member of the free fatty acid receptors family (FFAR), comprising of Gpr40, Gpr41, Gpr43, Gpr109a and Gpr120. These receptors are activated by free fatty acids. Gpr41, Gpr43 and Olfr78 are activated by SCFAs, while Gpr109a is activated by niacin and butyrate, Gpr40 and Gpr120 are activated by long chain fatty acids. It has been previously reported that Olfr78 and Gpr41 differentially modulate blood pressure (BP) in response to acute delivery of SCFAs. Olfr78 is expressed in vascular smooth muscle cells and Olfr78 KO mice are known to be hypotensive in comparison to Olfr78 WT mice. The broad goal of the work presented here was to better understand the role of Gpr41 in blood pressure regulation. It was hypothesized based on previous knowledge that Gpr41 KO mice would be hypertensive in comparison to Gpr41 WT mice. In the work presented, Gpr41 was localized to the vascular endothelium, in contrast to Olfr78, which is found in the vascular smooth muscle, initially by RT-PCR and substantiated by antibody staining of primary endothelial cells. Continuous telemetry blood pressure measurement in 3 – month old male Gpr41 KO and WT mice determined that Gpr41 KO mice exhibit systolic hypertension in comparison to Gpr41 WT mice. In addition, Gpr41 KO mice present with elevated pulse wave velocity at 6 months of age, but not at 3 months (time point of baseline blood pressure measurement). Examination of blood vessel tensile properties did not reveal differences in stiffness of intact aorta from Gpr41 KO and WT mice. Furthermore, Gpr41 KO mice do not exhibit salt sensitive hypertension, but interestingly, do not have an adaptive decrease in systolic pressure on a low salt diet, exhibited by the Gpr41 WT mice. In an attempt to understand the signaling behind SCFA – mediated vasodilation, it was observed that the vascular endothelium is essential for SCFA mediated vasodilation to occur, as vasodilation is absent in endothelium-denuded vessels ex vivo, consistent with a role for Gpr41 in decreasing blood pressure / mediating vasodilation. The work presented sheds light on the novel role of Gpr41 in the endothelium in blood pressure regulation. SCFA receptors expressed in both the vascular endothelium (Gpr41) and vascular smooth muscle (Olfr78) form a complex network to regulate BP in response to signals produced by the microbiota. In the future, better understanding of these pathways has the potential to further our understanding of BP regulation as a whole, as well as to more fully uncover the unique role of the gut microbiota in regulating both BP and vascular tone.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/58719
dc.languageen
dc.publisherJohns Hopkins University
dc.publisher.countryUSA
dc.subjectMicrobiota
dc.subjectBP regulation
dc.subjectendothelium
dc.subjectacetate
dc.subjectpropionate
dc.subjectGPCR
dc.subjectOlfr78
dc.subjectGpr41
dc.titleINTERPLAY OF MICROBIAL SHORT CHAIN FATTY ACIDS AND HOST G-PROTEIN COUPLED RECEPTORS IN BLOOD PRESSURE REGULATION
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentPhysiology
thesis.degree.disciplinePhysiology
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorSchool of Medicine
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
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