SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia

Shinoda, Masahiro; Tsuchida, Keiko; Maeda, Takeshi; Makino, Naoki

doi:10.1016/j.atherosclerosis.2006.04.021

Cited by 38 publications

(46 citation statements)

References 29 publications

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“…1 However, their endogenous role in VEGFR2 autophosphorylation under physiological condition remains unclear. SHP-1 is involved in tumor necrosis factor ␣-mediated prevention of VEGFR2 phosphorylation, 17 whereas SHP-2 inhibits tyrosine phosphorylation of VEGFR2 in ECs when they are cultured only on type I collagen. 18 HCPTPA overexpression attenuates VEGFR2 autophosphorylation, but this has not been studied with a loss-of-function approach.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, SHP-2 expression was not changed after ischemia, and SHP-2 siRNA had no effects on VEGFR2 autophosphorylation in cultured ECs, suggesting specific involvement of PTP1B in angiogenic responses in vitro and in vivo. Sugano et al 17 reported that SHP-1 protein is increased in a rat hindlimb ischemia model, which prevents tumor necrosis factor ␣-induced negative inhibitory effects on VEGF signaling. We also found that SHP-1 protein is increased after ischemia, but the extent of its increase is much less than that of PTP1B.…”

Section: Circulation Research May 23 2008mentioning

confidence: 99%

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Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Nakamura

Patrushev

Inomata

et al. 2008

Circulation Research

161

145

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Abstract-Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR)2 in tyrosine, which is followed by disruption of VE-cadherin-mediated cell-cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin-mediated cell-cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell-cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo. (Circ Res. 2008;102:1182-1191.)Key Words: protein tyrosine phosphatase 1B Ⅲ vascular endothelial growth factor Ⅲ endothelial cell Ⅲ cell-cell adhesions Ⅲ angiogenesis

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Section: Discussionmentioning

confidence: 99%

Section: Circulation Research May 23 2008mentioning

confidence: 99%

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Nakamura

Patrushev

Inomata

et al. 2008

Circulation Research

161

145

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“…These include genes that have been previously linked to atherosclerosis, such as Abcb4, Ctsk, Ptpn1, Ptpn6, Ptprc, and Msr1 (35)(36)(37)(38)(39)(40), and genes that we believe to be novel, like Atgr1a, Gpr65, Inpp5d, Mcoln2, Ctsz, Ptpre, Havcr2, and Galns. C3ar1, although not in the common plaque progression signature, is a G protein-coupled receptor and may also serve as a candidate drug target.…”

Section: Discussionmentioning

confidence: 98%

Identification and validation of genes affecting aortic lesions in mice

Yang¹,

Peterson²,

Thieringer³

et al. 2010

J. Clin. Invest.

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Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli hoodbased model selection method to infer genedisease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genomewide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosisrelated pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of cau sality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.

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“…SHP-1 and SHP-2 are cytoplasmic protein tyrosine phosphatases that negatively modulate VEGF-A signaling by dephosphorylating VEGF receptor-2 (Flk-1) (27), which is the receptor that mediates VEGF-Ainduced angiogenesis (51). Recently, knockdown of SHP-1 by siRNA was shown to augment angiogenesis in ischemic hindlimb (55). We therefore investigated SHP-1 and SHP-2.…”

Section: Balb/c Mice Have Reduced Hindlimb Perfusion Immediately Aftementioning

confidence: 99%

Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains

Chalothorn

Clayton

Zhang

et al. 2007

Physiological Genomics

188

277

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Substantial variability exists in collateral density and ischemia-induced collateral growth among species. To begin to probe the underlying mechanisms, which are unknown, we characterized two mouse strains with marked differences in both parameters. Immediately after femoral artery ligation, collateral and foot perfusion were lower in BALB/c than C57BL/6 ( P < 0.05 here and below), suggesting fewer pre-existing collaterals. This was confirmed with angiography and immunohistochemistry (∼35% fewer collaterals in the BALB/c's thigh). Recovery of hindlimb perfusion was attenuated in BALB/c, in association with 54% less collateral remodeling, reduced angiogenesis, greater ischemia, and more impaired hindlimb use. Densities of CD45+ and CD4+ leukocytes around collaterals increased similarly, but TNF-α expression was 50% lower in BALB/c, which may contribute to reduced collateral remodeling. In normal tissues, compared with C57BL/6, BALB/c exhibit an altered arterial branching pattern and, like skeletal muscle above, have 30% fewer collaterals in intestine and, remarkably, almost none in pial circulation, resulting in greatly impaired perfusion after cerebral artery occlusion. Ischemic induction of VEGF-A was attenuated in BALB/c. Analysis of a C57BL/6 × BALB/c recombinant inbred strain dataset identified a quantitative trait locus for VEGF-A mRNA abundance at or near the Vegfa locus that associates with lower expression in BALB/c. This suggests a cis-acting polymorphism in the Vegfa gene in BALB/c could contribute to reduced VEGF-A expression and, in turn, the above deficiencies in this strain. These findings suggest these strains offer a model to investigate genetic determinants of collateral formation and growth in ischemia.

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SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia

Cited by 38 publications

References 29 publications

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Identification and validation of genes affecting aortic lesions in mice

Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains

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