Upregulation of stromal cell–derived factor 1 (SDF-1) expression in microvasculature endothelial cells in retinal ischemia-reperfusion injury

Lai, Ping-Hong; Li, Tao; Yang, Jun; Xie, Chengyang; Zhu, Xiaobo; Xie, Hui; Ding, Xiaoyan; Lin, Shaofen; Tang, Shibo

doi:10.1007/s00417-008-0907-3

Cited by 29 publications

(23 citation statements)

References 29 publications

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“…SDF1 is a well-established hypoxia response in the mouse hindlimb ischemia model of ischemic-reperfusion injury 32 as well as in acute human limb muscle ischemia. 33 Therefore, to determine whether SDF1 expression during hypoxia occurred in an endothelial cell-autonomous fashion in vivo and whether endoglin levels regulated this response, endoglin-deficient and wild-type mice were subjected to right hindlimb femoral artery ligation.…”

Section: Endoglin Deficiency Promotes Vascular Tortuosity and Impairsmentioning

confidence: 99%

“…Hypoxia-dependent HIF1␣-mediated induction of SDF1 expression is well described in several vascular disease settings. 32 For example, in a model of burn wound healing, heterozygous HIF1␣-deficient mice exhibited diminished SDF1 levels and mounted an impaired burn wound response. This result suggests that SDF1 levels are critical to the healing process.…”

mentioning

confidence: 99%

“…30,39 Along with endoglin's up-regulation after ischemic injury, the reperfusion of tissues is initiated by hypoxia-dependent induction of SDF1 in endothelial cells. 32 During tissue repair, SDF1 provides an endothelial cell-derived signal that promotes recruitment of bone marrowderived progenitor cells 40 and their differentiation into pericytes. 15 These events contribute to endothelial cell quiescence and vessel maturation.…”

mentioning

confidence: 99%

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BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Young

Conley

Romero

et al. 2012

Blood

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BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia (HHT) and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained after BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways. These responses included the up-regulation of the chemokine CXCL12/SDF1 and down-regulation of its receptor CXCR4. Quantitative mass spectrometry identified additional secreted proteins, including the chemokine CXCL10/IP10. RNA knockdown of endoglin and ALK1 impaired SDF1/CXCR4 regulation by BMP9. Because of the association of SDF1 with ischemia, we analyzed its expression under hypoxia in response to BMP9 in vitro, and during the response to hindlimb ischemia, in endoglin-deficient mice. BMP9 and hypoxia were additive inducers of SDF1 expression. Moreover, the data suggest that endoglin deficiency impaired SDF1 expression in endothelial cells in vivo. Our data implicate BMP9 in regulation of the SDF1/CXCR4 chemokine axis in endothelial cells and point to a role for BMP9 signaling via endoglin in a switch from an SDF1-responsive autocrine phenotype to an SDF1 nonresponsive paracrine state that represses endothelial cell migration and may promote vessel maturation. IntroductionEndoglin directly interacts with the TGF-␤ receptors, 1 including ALK1, 2 and modulates TGF-␤ and bone morphogenetic protein (BMP) signaling. 3 Mutations in either endoglin 4 or ALK1 5 increase the risk of hereditary hemorrhagic telangiectasia (HHT1 and HHT2, respectively), whose symptoms include arteriovenous malformation, tissue ischemia, and reperfusion defects. 6 The ALK1-endoglin signaling complex in endothelial cells is activated by BMP9, 7 a circulating cytokine produced in the liver reticuloendothelium 8 and endothelial cells, including those lining the mouse aorta. 9 BMP9 interacts with endoglin and ALK1 to activate signaling pathways 7 that promote endothelial cell quiescence 10 and vessel maturation. 11 Several endothelial cell-derived factors, including BMP9, are known to regulate vessel maturation via paracrine recruitment of other cell types. 12 Moreover, our recent work using nonendothelial cells implicates endoglin in the regulation of tumor neoangiogenesis via the secreted insulin-like growth factor binding protein 4. 13 Therefore, elucidation of the role of BMP9 signaling, specifically in terms of its effects on the expression of endothelial cell-secreted factors, is needed to better understand the mechanisms by which BMP9 affects vessel maturation, integrity, the vascular response to injury, and how deficiency in either endoglin or ALK1 impacts vessel integrity and cause HHT.Stromal-derived factor 1 (SDF1, CXCL12) is a chemokine that signals via the chemokine receptor, CXCR4, to modulate hypoxiainduced angiogenesis. 14 SDF1 regulates both endothelial cellmediated paracrine signaling ...

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Section: Endoglin Deficiency Promotes Vascular Tortuosity and Impairsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Young

Conley

Romero

et al. 2012

Blood

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“…HRECs were isolated from tissue a patient undergoing corneal transfer surgery at Zhongshan Ophthalmic Center, Sun Yat-Sen University (Guangzhou, China) as previously described (10). Briefly, cells were grown in human endothelial serum free-medium (Gibco-BRL, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific, Hyclone, Logan, UT, USA), 5 µg̸l β-endothelial cell growth factor (β-ECGF; R&D Systems Inc., Minneapolis, MN, USA) and 1% (v̸v) penicillin-streptomycin (Gibco-BRL, Grand Island, NY, USA) at 37˚C in a 5% CO 2 and 95% air atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Translocation of protein kinase C δ contributes to the moderately high glucose-, but not hypoxia-induced proliferation in primary cultured human retinal endothelial cells

Liu

et al. 2014

Molecular Medicine Reports

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Diabetic retinopathy is one of the most common complications in patients with diabetes and affects ~75% of them within 15 years of the onset of the disease. Activation of protein kinase C (PKC) is a key feature of diabetes mellitus and may be involved in the pathogenesis of diabetic retinop-athy. The present study aimed to examine the translocation of protein kinase C (PKC) isoforms, which are triggered by high an moderately high glucose levels as well as hypoxic conditions. The underlying cell mechanisms of PKC translocation in primary cultured human retinal endothelial cells (HRECs) were also investigated. The expression levels of PKC isoforms were assessed using western blot analysis. Cell proliferation was determined using the MTT assay and DNA synthesis was assessed by bromodeoxyuridine incorporation. Translocation of PKC isoforms was examined by western blot analysis and immunofluorescence. The expression of PKC α, βI, βII, δ and ε was detected, while PKC ζ was not detected in HRECs. The results of the present study were consistent with the findings of a previous study by our group, reporting that moderately high glucose levels and hypoxia, but not high glucose levels, significantly increased cell proliferation. It was demonstrated that the PKC δ isoform was translocated from the cytosol to the membrane only under moderately high glucose conditions , while PKC α and ε isoforms were translocated from the cytosol to the membrane at high glucose conditions. In addition, PKC βI was translocated under all three conditions. Translocation of PKC βII was comparable among all groups. Furthermore, rottlerin, an inhibitor of PKC δ, blocked cell proliferation, which was induced by moderately high glucose levels, but not by hypoxia. Ro32-0432, an inhibitor of PKC α, βI and ε, did not significantly affect proliferation of HRECs in all treatment groups. In conclusion, the present study suggested that PKC α, βI, βII, δ and ε were expressed in primary cultured HRECs, whereas PKC ζ was not. Cell proliferation induced by moderately high glucose concentrations was associated with translocation of the PKC δ isoform; however, hypoxic conditions did not induce translocation.

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“…We know it is significantly upregulated in various experimental models of retinal disease and in patients with vascular retinopathies. [67][68][69][70] Several reports testify to the benefit of SDF-1-mediated mobilization of bone marrow-derived stem cells and their role in modifying experimental myocardial infarction through enhanced angiogenesis and improved cardiac function. [71][72][73][74] SDF-1 also appears to have other pertinent roles that add to its attraction as a therapeutic candidate to enhance stem cell behaviour.…”

Section: Feasibility Of Reparative Vasculogenesismentioning

confidence: 99%

Cell Therapy for Diabetic RetinopathyA Work in Progress

Kent¹

2012

US Endocrinology

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In the developed world, diabetic retinopathy (DR) is the leading cause of vision loss in the working population.1 Coupled with the fact that the prevalence of DR is expected to double by 2025, the impact on quality of life of affected individuals and the societal cost in general cannot be overstated. 2 The increasing burden on ophthalmic departments is similarly enormous, so the search for novel therapies has become imperative. Laser photocoagulation for DR has been the therapeutic gold standard for over a quarter of a century, while recently we have seen the introduction of intravitreally administered antiangiogenic therapy following the results of recently conducted clinical trials. 3-8Moreover, the recognition of the role of inflammation in DR has also focused the spotlight on the use of intravitreal steroids. 9-11 These therapies, though variously effective, are late-stage interventions that are administered when the disease may have been present for many years and when vision loss is imminent or may already have occurred.Thus, in the absence of a cure for diabetes, a treatment that could be delivered at an earlier stage when the risk of vision loss is still remote, that is safe, and that directly addresses the underlying pathology of the disease would be a giant step forward. As cell therapy satisfies these criteria, it has potential as a future treatment for DR. Terminology and DefinitionsThe terminology can be confusing when it comes to defining the various stem cell types. In the main, this article concentrates on what we currently understand to be endothelial progenitor cells (EPCs). These cells are derived from the bone marrow and were first isolated by Asahara et al. 12 We now know that when we use this term we are probably not referring to a single cell entity, but instead to a group of cells that are capable of differentiating down an endothelial cell route or lineage. 13 First, EPCs can be derived from hemangioblasts and express various cell markers, including vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34. 14 Second, EPCs are considered a subset of cells derived from bone marrow multipotent adult progenitor cells (MAPCs). While these also express VEGFR-2 and CD133, they lack CD34. 13 Finally, bone marrow-derived myelocytic/monocytic cells can also differentiate into EPCs, express CD14, and form mature endothelial cells that express von Willebrand factor, VEGFR-2, and CD45 in culture.14 All EPCs, regardless of their origin, take up acetylated low-density lipoprotein (LDL) and bind Ulex europaeus lectin 1 (UEA1). 15,16 Thus, in vivo, at least three groups of 'EPCs' can give rise to mature endothelial cells: hemangioblasts, MAPCs, and myelocytic/monocytic cells. 14In vitro EPCs can be isolated by using cell sorting, by exploiting immunotypic cell surface proteins, or by isolation of the mononuclear fraction of blood followed by cell culture using different substrates and media. Isolation of EPCs using cell sorting is challenging, mainly because there is still ambiguity as to...

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Upregulation of stromal cell–derived factor 1 (SDF-1) expression in microvasculature endothelial cells in retinal ischemia-reperfusion injury

Abstract: The results of our study indicate that endogenous SDF-1 is up-regulated in retinal microvasculature suffering ischemia insult, and that microvasculature endothelial cells are potential contributors for generation of SDF-1 in ischemic retina.

Cited by 29 publications

References 29 publications

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Translocation of protein kinase C δ contributes to the moderately high glucose-, but not hypoxia-induced proliferation in primary cultured human retinal endothelial cells

Cell Therapy for Diabetic RetinopathyA Work in Progress

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Upregulation of stromal cell–derived factor 1 (SDF-1) expression in microvasculature endothelial cells in retinal ischemia-reperfusion injury

Abstract: The results of our study indicate that endogenous SDF-1 is up-regulated in retinal microvasculature suffering ischemia insult, and that microvasculature endothelial cells are potential contributors for generation of SDF-1 in ischemic retina.

Cited by 29 publications

References 29 publications

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

BMP9 regulates endoglin-dependent chemokine responses in endothelial cells

Translocation of protein kinase C δ contributes to the moderately high glucose-, but not hypoxia-induced proliferation in primary cultured human retinal endothelial cells

Cell Therapy for Diabetic RetinopathyA Work in Progress

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Product

Resources

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Cell Therapy for Diabetic RetinopathyA Work in Progress