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Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.

ABSTRACT: During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial-derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1? (HIF-1?) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduced adenovirus mediated expression of constitutively active HIF-1? (AdcaHIF1?) into the embryonic avian epicardium where the vascular precursors reside. We found that introducing caHIF1? into the epicardial mesothelium prevented EPDCs from proper migration into the myocardium. In vitro collagen gel assays and ex vivo organ culture data further confirmed that infection with AdcaHIF1? impaired the ability of EPDCs to invade. However, the proficiency of epicardial cells to undergo EMT was enhanced while the movement of EPDCs within the sub-epicardium and their differentiation into smooth muscle cells were not disrupted by caHIF1?. We also showed that the transcript level of Flt-1 (VEGFR1), which can act as a VEGF signaling inhibitor, increased several fold after introducing caHIF1? into epicardial cells. Blocking the activation of the VEGF pathway in epicardial cells recapitulated the inhibition of EPDC invasion. These results suggest that caHIF1? mediated up-regulation of Flt-1, which blocks the activation of the VEGF pathway, is responsible for the inhibition of EPDC myocardial migration. In conclusion, our studies demonstrate that HIF signaling potentially regulates the degree of epicardial EMT and the extent of EPDC migration into the myocardium, both of which are likely critical in patterning the coronary vasculature during early cardiac vasculogenesis. These signals could explain why the larger coronaries appear and remain on the epicardial surface.

SUBMITTER: Tao J

PROVIDER: S-EPMC3602346 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.

Tao Jiayi J Doughman Yongqiu Y Yang Ke K Ramirez-Bergeron Diana D Watanabe Michiko M

Developmental biology 20130204 2

During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial-derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1α (HIF-1α) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduce ...[more]

PMID: 23384563

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Project description:BackgroundEndothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms.MethodsWe conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry.ResultsHigh glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors.ConclusionsThese findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.

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Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.

Publications

Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.

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