Synthesis and secretion of thrombospondin by cultured human endothelial cells.

Mosher, DF; Doyle, Mary Jean; Jaffe, Eric

doi:10.1083/jcb.93.2.343

Cited by 298 publications

(135 citation statements)

References 47 publications

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“…However, we cannot rule out the possibility that subsets of ECs not examined in this study express TSP2, or that ECs can be induced to express TSP2 with specific stimuli. In this respect, TSP2 differs from TSP1 in that TSP1 is more prominently expressed in endothelial cells during embryogenesis (Iruela-Arispe et al, 1993) and is synthesized in significant amounts by cultured ECs (McPherson et al, 1981;Mosher et al, 1982). Thus, unlike TSP2, TSP1 seems to be an autocrine inhibitor of EC function (Iruela-Arispe et al, 1991;DiPietro et al, 1994;Tolsma et al, 1997).…”

Section: Tsp2 Inhibits Ec Proliferationmentioning

confidence: 99%

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Armstrong¹,

Björkblom²,

Hankenson³

et al. 2002

MBoC

103

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The matricellular protein thrombospondin 2 (TSP2) regulates a variety of cell-matrix interactions. A prominent feature of TSP2-null mice is increased microvascular density, particularly in connective tissues synthesized after injury. We investigated the cellular basis for the regulation of angiogenesis by TSP2 in cultures of murine and human fibroblasts and endothelial cells. Fibroblasts isolated from murine and human dermis synthesize TSP2 mRNA and secrete significant amounts of immunoreactive TSP2, whereas endothelial cells from mouse lung and human dermis did not synthesize TSP2 mRNA or protein. Recombinant mouse TSP2 inhibited growth of human microvascular endothelial cells (HMVECs) mediated by basic fibroblast growth factor, insulin-like growth factor-1, epidermal growth factor, and vascular endothelial growth factor (VEGF). HMVECs exposed to TSP2 in the presence of these growth factors had a decreased proportion of cells in S and G 2 /M phases. HMVECs cultured with a combination of basic fibroblast growth factor, insulin-like growth factor-1, and epidermal growth factor displayed an increased proportion of nonviable cells in the presence of TSP2, but the addition of VEGF blocked this TSP2-mediated impairment of cell viability. TSP2-mediated inhibition of DNA synthesis by HMVECs in the presence of VEGF was not affected by the broadspectrum caspase inhibitor zVAD-fmk. Similar findings were obtained with TSP1. Taken together, these observations indicate that either TSP2 or TSP1 can inhibit HMVEC proliferation by inhibition of cell cycle progression and induction of cell death, but the mechanisms responsible for TSP2-mediated inhibition of cell cycle progression are independent from those leading to cell death. INTRODUCTIONThe process of wound healing is highly dependent on angiogenesis to provide a vascular network for the regenerating tissue. The study of mechanisms governing vascularization of healing connective tissues has primarily focused on proangiogenic factors occurring early in the wound-healing process. Degranulating platelets and a fibrin clot provide growth and chemotactic factors and an adhesive substrate for initial influx of endothelial cells (ECs) (Singer and Clark, 1999;Tonnesen et al., 2000). Infiltrating inflammatory cells, such as macrophages, appear at the wound site shortly after the wounding event and are also potent sources of proangiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (Sunderkö tter et al., 1994). A number of these factors also induce migration of fibroblasts into the wound area and stimulate fibroblasts to deposit extracellular matrix (Kalluri and Sukhatme, 2000). The direct influence of fibroblasts on ECs in determining the vascularity of the healing wound is less clear. Regression of blood vessels seen in the resolution phase of a wound, in which fibroblasts become the predominant cell type, suggests an inhibitory role for fibroblasts in the angiogenic process (Kyriakides et al., 1999b).A large number of factors...

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Section: Tsp2 Inhibits Ec Proliferationmentioning

confidence: 99%

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Armstrong¹,

Björkblom²,

Hankenson³

et al. 2002

MBoC

103

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“…It was initially isolated from platelets and megakaryocytes [28], but was later detected in several cell types such as macrophages and adipocytes [21,22,30,32]. Nowadays, it is known that TSP-1 is a multifunctional protein composed by multiple structural domains [5,10], and it has been especially related with several anti-angiogenic pathways [20,23,24].…”

Section: Introductionmentioning

confidence: 99%

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

et al. 2011

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Thrombospondin 1 (TSP-1), an anti-angiogenic factor and TGF-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin-resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow (C) or a high fat diet (HFD) for 50 days, were isolated and incubated (24-72 h) in low (LG; 5.6 mM) or high (HG; 25 mM) glucose, in presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin-resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulinresistant adipocytes. The difference between expression and secretion patterns suggests a post-transcriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

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“…The 160/180-and 120-kDa fibronectin fragments were generated as described . Vitronectin (Yatohgo et al, 1988), thrombospondin-1 (Mosher et al, 1982), and a fusion protein containing GST linked to fibronectin's III-9 and III-10 modules (GST/III-9,10; Hocking et al, 1996) were prepared as described previously.…”

Section: Proteinsmentioning

confidence: 99%

Fibronectin Polymerization Regulates the Composition and Stability of Extracellular Matrix Fibrils and Cell-Matrix Adhesions

Sottile

Hocking

2002

MBoC

552

510

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Remodeling of extracellular matrices occurs during development, wound healing, and in a variety of pathological processes including atherosclerosis, ischemic injury, and angiogenesis. Thus, identifying factors that control the balance between matrix deposition and degradation during tissue remodeling is essential for understanding mechanisms that regulate a variety of normal and pathological processes. Using fibronectin-null cells, we found that fibronectin polymerization into the extracellular matrix is required for the deposition of collagen-I and thrombospondin-1 and that the maintenance of extracellular matrix fibronectin fibrils requires the continual polymerization of a fibronectin matrix. Further, integrin ligation alone is not sufficient to maintain extracellular matrix fibronectin in the absence of fibronectin deposition. Our data also demonstrate that the retention of thrombospondin-1 and collagen I into fibrillar structures within the extracellular matrix depends on an intact fibronectin matrix. An intact fibronectin matrix is also critical for maintaining the composition of cell-matrix adhesion sites; in the absence of fibronectin and fibronectin polymerization, neither ␣5␤1 integrin nor tensin localize to fibrillar cell-matrix adhesion sites. These data indicate that fibronectin polymerization is a critical regulator of extracellular matrix organization and stability. The ability of fibronectin polymerization to act as a switch that controls the organization and composition of the extracellular matrix and cell-matrix adhesion sites provides cells with a means of precisely controlling cell-extracellular matrix signaling events that regulate many aspects of cell behavior including cell proliferation, migration, and differentiation. INTRODUCTIONExtracellular matrix remodeling plays an important role during development, wound healing, atherosclerosis, ischemic injury, and angiogenesis. Perturbing matrix remodeling by preventing the turnover of collagen I or by altering the levels of matrix-degrading proteases or protease inhibitors has been shown to result in fibrosis, arthritis, reduced angiogenesis, and developmental abnormalities (Liu et al., 1995;Vu et al., 1998;Holmbeck et al., 1999;Ducharme et al., 2000). In normal adult tissue, some extracellular matrix components such as elastin and fibrillar collagen have half lives of months to years (Krane, 1985;Debelle and Tamburro, 1999). Other extracellular matrix components, such as proteoglycans, thrombospondin-1 and -2, and vitronectin, can be endocytosed and degraded in the lysosomes (McKeownLongo et al., 1984;Yanagishita and Hascall, 1984; MurphyUllrich and Mosher, 1987;Hausser et al., 1992;Godyna et al., 1995a;Pijuan-Thompson and Gladson, 1997;Memmo and McKeown-Longo, 1998). Extracellular matrix molecules can also be degraded extracellularly by proteases such as matrix metalloproteinases (MMPs), plasminogen activators, and plasmin (Hynes, 1990;Marchina and Barlati, 1996;Shapiro, 1998).Recent data indicate that polymerized forms of extracellular matri...

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Synthesis and secretion of thrombospondin by cultured human endothelial cells.

Cited by 298 publications

References 47 publications

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

Fibronectin Polymerization Regulates the Composition and Stability of Extracellular Matrix Fibrils and Cell-Matrix Adhesions

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