title: Origin-specific epigenetic program correlates with vascular bed-specific differences in Rgs5 expression.
abstract: Cells from multiple origins contribute to vascular smooth muscle cell (VSMC) development. Phenotypic heterogeneity of VSMCs is associated with their point of developmental origin; however, the mechanisms driving such differences are unknown. We here examined the mechanisms controlling vascular bed-specific differences in Rgs5 expression during development. Rgs5 levels were similar across different regions of the vasculature in neonatal animals but were >15-fold higher in descending aortas compared with carotid arteries of adult mice. Thus, vessel bed-specific changes in regulation of Rgs5 expression occurred during vessel maturation. Examination of adult Rgs5-LacZ reporter mice revealed lower Rgs5 expression in VSMCs originating from the third (carotid artery) branchial arch compared with those originating in the fourth and sixth (aortic B segment, right subclavian, and ductus arteriosus) branchial arches. Indeed, a mosaic Rgs5 expression pattern, with discreet LacZ boundaries between VSMCs derived from different developmental origins, was observed. Furthermore, Rgs5-LacZ expression was correlated with the site of VSMC origin (splanchic mesoderm ≈ local mesenchyme > somites > proepicardium > mesothelium). Surprisingly, Rgs5 reporter activity in cultured carotid artery- and descending aorta-derived cells did not recapitulate the differences observed in vivo. Consistent with a developmental origin-specific epigenetic mechanism driving the observed expression differences in vivo, the Rgs5 promoter showed increased methylation on CpG dinucleotides in carotid arteries compared with that in descending aortas in adult but not in neonatal mice. In vitro methylation of the Rgs5 promoter confirmed that its activity is sensitive to transcriptional down-regulation by CpG methylation. These data suggest that an origin-dependent epigenetic program regulates vascular bed- and maturation state-dependent regulation of VSMC-specific gene transcription.
authors.affiliation: Department of Physiology, Heart, and Stroke, University of Toronto, Toronto, ON Canada.
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Gu
authors.forename: Basil
authors.initials: B
authors.lastname: Al-Sabeq
authors.forename: Sean
authors.initials: S
authors.lastname: Wang
authors.forename: Janet
authors.initials: J
authors.lastname: He
authors.forename: Alex
authors.initials: A
authors.lastname: Tam
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifelli
authors.forename: Nurit
authors.initials: N
authors.lastname: Mathalone
authors.forename: Sam
authors.initials: S
authors.lastname: Tirgari
authors.forename: Shelley
authors.initials: S
authors.lastname: Boyd
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
mesh_terms: D000367:Age Factors; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D002339:Carotid Arteries / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020710:RGS Proteins; D012333:RNA, Messenger; C105346:Rgs5 protein, mouse