Thrombospondin‐1–deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia‐mediated vessel obliteration

Wang, Shoujian; Wu, Zhifeng; Sorenson, Christine M.; Lawler, Jack; Sheibani, Nader

doi:10.1002/dvdy.10412

Cited by 119 publications

(169 citation statements)

References 28 publications

(49 reference statements)

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“…TSP-1 is a secreted glycoprotein, member of the serine protease inhibitor family that binds to the extracellular matrix, inhibits NO signaling, and modulates vascular cell behavior with inhibition of angiogenesis (Isenberg et al 2008). TSP-1K/K mice had increased retinal vascular density (Wang et al 2003), and inhibition of TSP-1 improved vascular engraftment of pancreatic islets (Olerud et al 2008). We also found that serpin B5/maspin known to block VEGF/b-FGF-induced vascular endothelial cell migration and to inhibit angiogenesis (Bailey et al 2006) was increased.…”

Section: Discussionsupporting

confidence: 57%

Glucose inhibits angiogenesis of isolated human pancreatic islets

Dubois

Madec

Mesnier

et al. 2010

Journal of Molecular Endocrinology

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Owing to strong interactions between pancreatic islets and the surrounding capillary network, we hypothesized that high glucose concentrations might affect key angiogenesis factors from isolated human islets, thus contributing to b-cell failure in diabetes. Human islets from eight distinct donors were studied following 96 h in culture in the presence of normal (5 . 5 mmol/l) or high (16 . 7 mmol/l) glucose concentrations. Similar studies were performed with HUVECs. Human angiogenesis-related genes and corresponding proteins were studied by real-time quantitative PCR (RT-qPCR) and protein arrays respectively. Angiogenesis and proliferation assays were also performed with HUVECs under the same culture conditions. RT-qPCR and proteome analysis of human islets incubated with 16 . 7 mM/l glucose revealed a significant decrease in pro-angiogenic factors including vascular endothelial growth factor (VEGF) mRNA by 20% and VEGF protein levels by 42% as well as additional proteins such as fibroblast growth factor-4 by 41%, MMP9 by 18%, monocyte chemoattractant protein-1 by 21%, and prolactin by 25%. In contrast, we observed a 17% increase in thrombospondin-1 (TSP-1, listed as THBS1 in the HUGO database) and a 37% increase in angiotensinogen gene expression levels, but neither angiotensin-converting enzyme nor angiotensin II type 1 receptor gene expression was affected. The amounts of anti-angiogenic proteins such as TSP-1 and serpin B5/maspin were also increased by 70 and 98% respectively as well as endostatin by 63%. Angiogenesis assays of HUVECS in the presence of high glucose concentrations revealed a 30% decrease in tree-like tubular network formation. These data suggest that glucose reduces key factors of islet angiogenesis, which might exacerbate b-cell failure.

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Section: Discussionsupporting

confidence: 57%

Glucose inhibits angiogenesis of isolated human pancreatic islets

Dubois

Madec

Mesnier

et al. 2010

Journal of Molecular Endocrinology

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“…High expression of TSP-1 in RPE in normoglycemic conditions is consistent with the anatomical position of RPE in the eye, where TSP-1, a potent antiangiogenic protein, may participate in the maintenance of the normal density of microvessels in the retina and choroid. The expression of TSP-1 in the normal eye and its decreased expression in the diabetic eye were reported, as well as increased vascularity in the retina of TSP-1-deficient animals (28,30).…”

Section: Discussionmentioning

confidence: 96%

“…Because TSP-1 is a potent antiangiogenic agent that in the normal eye may prevent uncontrolled growth of microvessels, such down-regulation of TSP-1 in the diabetic eye suggests its involvement in diabetic retinopathy. A direct effect of TSP-1 deficiency on retinal vascularity has been demonstrated recently in TSP-1-deficient mice (30).…”

mentioning

confidence: 81%

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

Bhattacharyya

Marinic

Krukovets

et al. 2008

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell-and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This downregulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cellspecific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.Despite the significant advances in the therapeutic methods to control blood glucose and insulin levels in diabetic patients, the precise regulation of these levels remains a problem. Vascular diabetic complications remain most prevalent and dangerous and account for the greatest numbers of deaths and hospitalizations in diabetic patients. The molecular basis for the vascular complications of diabetes is not well understood. Recent reports indicate that both microvascular and macrovascular complications of diabetes correlate directly with glucose levels in both patients and animal models (1-5). Some of these reports revealed the pathogenic role of impaired glucose tolerance and post-prandial hyperglycemia even in the absence of diabetes, e.g. (6). In vascular cells, glucose regulates expression of many genes that have been linked to the development of atherosclerosis or abnormal angiogenesis (reviewed in Ref. 7). One of them is thrombospondin-1 (TSP-1), 3 a cell matrix protein implicated in both atherogenesis (8 -12) and angiogenesis (13)(14)(15)(16)(17)(18)(19). Several lines of evidence indicate that TSP-1 may represent a lin...

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“…Glomerular and renal tubulointerstitial expression of THBS1 has also been reported in developing kidneys and diseased kidneys 29,30 . In retina of P28 mice, newly formed vessels regressed in the wild-type, while vascular density was increased in mice with THBS1 deficiency 31 . In line with these observations, our findings that ANGPT2 and THBS1 are significantly up-regulated at postnatal day 14 and preferentially in superficial immature glomeruli suggest a maturational control for excessive glomerular vasculature and a physiological response to functional changes of these glomeruli at that developmental stage.…”

Section: Discussionmentioning

confidence: 95%

Erratum: Maturational regression of glomeruli determines the nephron population in normal mice

2014

Pediatr Res

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Thrombospondin‐1–deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia‐mediated vessel obliteration

Abstract: Thrombospondin-1 (TSP1) is a natural inhibitor of angiogenesis. Its expression is most

Cited by 119 publications

References 28 publications

Glucose inhibits angiogenesis of isolated human pancreatic islets

Glucose inhibits angiogenesis of isolated human pancreatic islets

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

Erratum: Maturational regression of glomeruli determines the nephron population in normal mice

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