Overexpression of Angiopoietin-1 Increases CD133+/c-kit+ Cells and Reduces Myocardial Apoptosis in db/db Mouse Infarcted Hearts

Zeng, Heng; Li, Lanfang; Chen, Jianxiong

doi:10.1371/journal.pone.0035905

Cited by 40 publications

(38 citation statements)

References 44 publications

(60 reference statements)

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“…To the best of our knowledge, there are no other reports on the direct effect of Ang-1 on keratinocyte migration, but there are data showing that angiopoietin like-4 plays a role in keratinocyte migration. Mice deficient in angiopoietin like-4 have impaired keratinocyte migration and delayed wound re-epithelialization (56). …”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-1 improves endothelial progenitor cell–dependent neovascularization in diabetic wounds

Balaji

Han

Moles

et al. 2015

Surgery

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Background The diabetic phenotype of wound healing is in part characterized by impaired neovascularization and deficient endothelial progenitor cell (EPC) recruitment. Angiopoietin-1 (Ang-1) is a potent mobilizer of EPCs from the bone marrow (BM). A suggested mechanism for EPC mobilization from the BM is mediated by matrix metalloproteinase 9 (MMP-9) and stem cell factor (SCF). Taken together, we hypothesized that overexpression of Ang-1 in diabetic wounds will recruit EPCs and improve neovascularization and wound healing. Methods An endothelial lineage BM-labeled murine model of diabetes was developed to track BM-derived EPCs. FVBN mice were lethally irradiated and then reconstituted with BM from syngeneic Tie2/LacZ donor mice. Diabetes was induced with streptozotocin. Dorsal wounds in BM-transplanted (BMT) mice were treated with Ad-Ang-1, Ad-GFP, or PBS. At day 7 post injury, wounds were harvested and analyzed. A similar experiment was conducted in EPC mobilization deficient MMP-9 −/− mice to determine whether the effects of Ang-1 were EPC-dependent. Results Overexpression of Ang-1 resulted in significantly improved re-epithelialization, neovascularization, and EPC recruitment in diabetic BMT wounds at day 7. Ang-1 treatment resulted in increased serum levels of proMMP-9 and SCF, but had no effect on vascular endothelial growth factor (VEGF) levels. According to our FACS results, peripheral blood EPC (CD34+/Cd133+/Flk1+) counts at day 3 post wounding showed impaired EPC mobilization in MMP-9 −/− mice, when compared with those of wild type controls. EPC mobilization was rescued by SCF administration, validating this model for EPC-mobilization deficient mechanistic studies. In MMP-9 −/− mice, Ad-Ang-1 accelerated re-epithelialization in a similar manner, but had no effect on neovascularization. Conclusion Our results show that Ang-1 administration results in improved neovascularization which is dependent on EPC recruitment and has direct effects on wound re-epithelialization. These data may represent a novel strategy to correct the phenotype of impaired diabetic neovascularization and may improve diabetic wound healing.

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Section: Discussionmentioning

confidence: 99%

Angiopoietin-1 improves endothelial progenitor cell–dependent neovascularization in diabetic wounds

Balaji

Han

Moles

et al. 2015

Surgery

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“…71 Overexpression of Ang-1 increases CXCR4/CXCL12 expression and promotes CD133 + cell recruitment into ischemic diabetic hearts. 72 Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors and their ephrin ligands are key regulators of vascular development. EphB4 activation with an ephrin-B2-Fc chimeric protein increases the angiogenic potential of human EPCs.…”

Section: Diabetes Mellitus and Bm-derived Cell Recruitmentmentioning

confidence: 99%

Diabetes Mellitus and Ischemic Diseases

Howangyin

Silvestre

2014

ATVB

126

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Hypoxia-Inducible Factor 1Hypoxia, at least in part through activation of the hypoxiainducible factor 1 (HIF-1) α-related pathways, controls all steps of the postischemic revascularization process. Recent studies uncover that destabilization of HIF-1 is most likely the event that transduces hyperglycemia into the loss of the cellular response to hypoxia in most diabetic complications.2 Levels of HIF-1α are decreased in biopsies from foot ulcers of patients with diabetes mellitus as compared with venous ulcers that share the same hypoxic environment but are not exposed to hyperglycemia.3 Downregulation of HIF-1 in response to hyperglycemia also seems to account for the decreased collateral growth triggered by myocardial ischemia in patients with © 2014 American Heart Association, Inc. Abstract-In patients with diabetes mellitus, the ability of ischemic tissue to synchronize the molecular and cellular events leading to restoration of tissue perfusion in response to the atherosclerotic occlusion of a patent artery is markedly impaired. As a consequence, adverse tissue remodeling and the extent of ischemic injury are intensified, leading to increased morbidity and mortality. Growing evidence from preclinical and clinical studies has implicated alterations in hypoxia-inducible factor 1 levels in the abrogation of proangiogenic pathways, including vascular endothelial growth factor A/phosphoinositide 3′ kinase/AKT/endothelial nitric oxide synthase and in the activation of antiangiogenic signals characterized by accumulation of advanced glycation end products, reactive oxygen species overproduction, and endoplasmic reticulum stress. In addition, the diabetic milieu shows a switch toward proinflammatory antiregenerative pathways. Finally, the mobilization, subsequent recruitment, and the proangiogenic potential of the different subsets of angiogenesis-promoting bone marrow-derived cells are markedly impaired in the diabetic environment. In this review, we will give an overview of the current understanding on the signaling molecules contributing to the diabetes mellitusinduced impairment of postischemic revascularization mainly in the setting of myocardial infarction or critical limb ischemia. (Arterioscler Thromb Vasc Biol. 2014;34:1126-1135.)

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“…In support of that hypothesis, we have shown by immunoblotting in a murine model of ischemic cardiomyopathy that direct borderzone intramyocardial injections of ESA at the time of infarct significantly upregulates tissue levels of Angiopoietin-1, indicative of an ongoing angiogenic process as late as two weeks after infarction and treatment (Zeng et al 2012). One could argue that the mechanism responsible for the upregulated angiogenic activity is an exaggerated inflammatory response resulting from the injection of ESA or even SDF.…”

Section: Discussion and Resultsmentioning

confidence: 77%

Re-Engineered Stromal Cell–Derived Factor-1α and the Future of Translatable Angiogenic Polypeptide Design

Hiesinger

Goldstone

Woo

2012

Trends in Cardiovascular Medicine

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Smaller engineered analogs of angiogenic cytokines may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and most importantly the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the SDF molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low molecular weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than recombinant human SDF both in vitro and in a murine model of ischemic heart failure.

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Overexpression of Angiopoietin-1 Increases CD133+/c-kit+ Cells and Reduces Myocardial Apoptosis in db/db Mouse Infarcted Hearts

Cited by 40 publications

References 44 publications

Angiopoietin-1 improves endothelial progenitor cell–dependent neovascularization in diabetic wounds

Angiopoietin-1 improves endothelial progenitor cell–dependent neovascularization in diabetic wounds

Diabetes Mellitus and Ischemic Diseases

Re-Engineered Stromal Cell–Derived Factor-1α and the Future of Translatable Angiogenic Polypeptide Design

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