Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia

Han, Yong Seop; Yang, Ke; Proweller, Aaron; Jain, Mukesh K.; Ramírez-Bergeron, Diana L.

doi:10.1007/s10456-012-9269-x

Cited by 19 publications

(25 citation statements)

References 59 publications

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“…Furthermore, CD31 + /PH3 + cell quantification revealed reduced numbers of proliferating ECs in Arnt ΔiEC wounds relative to controls (Figure 1G, S1C) . While these results confirm reports that HIF is essential in promoting the maintenance, migration, and proliferation of endothelial cells, we hypothesize that reduced infiltration of endothelial progenitor cells as part of the neoangiogenic response may contribute to the delay in wound healing 22, 28 .…”

Section: Resultssupporting

confidence: 88%

“…The efficiency of this Cre mouse was previously reported to result in about 70% deletion in the adult endothelium, whereas a low percentage (< 0.3%) in bone marrow cells 21 . Arnt loxP/loxP : VeCadherin-Cre TM+ 8–12 week old mice were injected with Tamoxifen for 10 days and deletion efficiency was assessed by the amplification of a null allele band from genomic tail DNA (Arnt iΔEC ) 22 . This genetic approach inhibits all canonical-HIF transcriptional activity and deletion is limited to the course of tamoxifen injections.…”

Section: Resultsmentioning

confidence: 99%

“…Tamoxifen (TM; Sigma) was dissolved in a sunflower oil/ethanol (10:1) mixture at 20 mg/ml. One mg of TM was injected daily intraperitoneally into 8 week old Arnt loxP/loxP :: VecadCre ERT2 mice and control littermates (either Arnt loxP/+ :: VecadCre ERT2 or Arnt loxP/loxP ) for ten consecutive days and Arnt- deletion was detected by PCR 22 .…”

Section: Methodsmentioning

confidence: 99%

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Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

et al. 2014

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The recruitment and homing of circulating bone marrow (BM)–derived cells include endothelial progenitor cells (EPCs) that are critical to neovascularization and tissue regeneration of various vascular pathologies. We report here that conditional inactivation of Hypoxia Inducible Factor’s (HIF) transcriptional activity in the endothelium of adult mice (ArntΔiEC mice) results in a disturbance of infiltrating cells, a hallmark of neoangiogenesis, during the early phases of wound healing. Cutaneous biopsy punches show distinct migration of CD31+ cells into wounds of control mice by 36 hours. However, a significant decline in numbers of infiltrating cells with immature vascular markers, as well as decreased transcript levels of genes associated with their expression and recruitment were identified in wounds of ArntΔiEC mice. Matrigel plug assays further confirmed neoangiogenic deficiencies alongside a reduction in numbers of proangiogenic progenitor cells from bone marrow and peripheral blood samples of rVEGF treated ArntΔiEC mice. In addition to HIF’s autocrine requirements in endothelial cells, our data implicate that extrinsic microenvironmental cues provided by endothelial- HIF are pivotal for early migration of proangiogenic cells, including those involved in wound healing.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

et al. 2014

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“…First, HIF1 activation increases EC sensitivity to angiogenic signals, via upregulation of VEGFR-1, 32 VEGFR-2, 33 and Dll4. 34 Short exposure or moderate levels of hypoxia (2.5% oxygen) enhances in vitro tube formation by EC 22,35 ; this response is HIF1-mediated, since EC isolated from mice depleted of the HIFb subunit showed defective migration, proliferation, and tube formation. 22 To confirm this role in the context of engineered tissue, one would need to knock-down HIF1a in transplanted EC.…”

Section: Graft-derived Vascularization May Be Governed By a Hif1-medimentioning

confidence: 99%

“…18 As a master regulator of cellular response to stresses like hypoxia, HIF1a affects the transcription of numerous genes related to angiogenesis, survival, proliferation, and glucose metabolism. [19][20][21] In hypoxia, HIF1 mediates EC survival and tube formation, 22,23 augments MSC-secreted paracrine factors, [24][25][26] and myeloid cell recruitment to ischemic sites. 16,17,[27][28][29][30][31] Together, these cells orchestrate an angiogenic response to reestablish oxygenation within the ischemic tissue.…”

Section: Introductionmentioning

confidence: 99%

Tuning Graft- and Host-Derived Vascularization in Modular Tissue Constructs: A Potential Role of HIF1 Activation

Lam

Sefton²

2015

Tissue Engineering Part A

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A better understanding of the factors governing the vascularization of engineered tissues is crucial for their advancement as therapeutic platforms. Here, we studied the effect of implant volume and cell densities on the in vivo vascularization of modular engineered tissue constructs. Sub-millimeter collagen modules containing adipose-derived mesenchymal stromal cells (adMSC) and enveloped by human umbilical vein endothelial cells (HUVEC) were subcutaneously implanted in severe-combined immunodeficient mice with a beige-mutation (SCID-bg) mice. Implant volume and cell density was varied relative to a base case, defined as a 0.01 mL implant containing 1.5×10(7) adMSC/mL and 3.9×10(6) HUVEC/mL. At 7 and 14 days post-transplantation, the constructs were harvested for immunohistochemical analysis of total (CD31(+)) and graft-derived (UEA1(+)) vessel formation, hypoxia-inducible factor 1-alpha (HIF1α) expression, infiltration of host-derived leukocytes (CD45), and macrophages (F4/80). Implant volume and cell density affected the relative contributions of host- versus graft-derived vascularization, highlighting that different mechanisms underlie the two processes. Graft-derived vessel formation was most rapid and robust in implants with high HIF1α expression, namely large volume implants and implants with high adMSC and HUVEC density (p<0.01 compared to base case at day 7). Many HIF1α(+) cells were vessel-lining HUVEC, suggesting that HIF1 activation may be key to vessel assembly in the graft. Host vessel ingrowth, however, dominated the vascularization of small volume implants (of high and low adMSC density alike), which showed low HIF1α expression at day 7. Host vessels were sustained to day 14 when adMSC density alone was increased, presumably due to increased paracrine secretions. This study points to a potential role of HIF1 activation in the vascularization of tissue constructs, which may be harnessed to engineer robust vessels for therapeutic applications.

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The ethics of placebo treatment for patients with acute exacerbation of chronic hepatitis B

et al. 2011

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Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia

Cited by 19 publications

References 59 publications

Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

Tuning Graft- and Host-Derived Vascularization in Modular Tissue Constructs: A Potential Role of HIF1 Activation

The ethics of placebo treatment for patients with acute exacerbation of chronic hepatitis B

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