Origin‐specific epigenetic program correlates with vascular bed‐specific differences inRgs5expression

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.

Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone

“…origins of vasculogenic cells (54,79). Indeed, vascular progenitor cells can arise from neural crest cells (32,41), splanchnic mesoderm (76), somitic mesoderm (74), and mesothelial cells (60).…”

Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult

“…Interestingly, differences in VSMC characteristics such as gene expression have been attributed to their embryonic origin [25]. Also, studies suggest that when vessels prone to atherosclerosis are placed in a vascular region that does not typically develop atherosclerosis, they retain their predisposition to disease [26].…”

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

“…149 This difference led to a specific gene expression pattern in embrionic VSMCs, which converge in a unique phenotype in adult vessels, 150 although it has been proven that some genes can show peculiar expression patterns in different vascular beds. 151 Moreover, it was also reported that several cell types activate a subset of embronic genes in response to injury [152][153][154] ; this could provide new insights about the mechanism by which equal cells in different vessels (ie, aorta, carotid) respond in disparate ways to similar stimuli.…”