Vascular Endothelial Growth Factor Increases Release of Gelatinase A and Decreases Release of Tissue Inhibitor of Metalloproteinases by Microvascular Endothelial Cellsin Vitro

Lamoreaux, William J.; Fitzgerald, Malinda E.C.; Reiner, Anton; Hasty, Karen A.; Charles, Steven T.

doi:10.1006/mvre.1997.2056

Cited by 253 publications

(147 citation statements)

References 33 publications

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“…These two factors are considered the main angiogenic modulators stimulating several endothelial cell functions relevant to angiogenesis, including invasiveness and production of matrix-degrading enzymes. 10,12,28,29 While confirming the stimulatory effect of these factors on the proteolytic activity of endothelial cells, our study provides the first evidence that angiogenic factors stimulate the secretion of MMPs as membrane vesicle components.…”

Section: Discussionsupporting

confidence: 71%

Shedding of the Matrix Metalloproteinases MMP-2, MMP-9, and MT1-MMP as Membrane Vesicle-Associated Components by Endothelial Cells

Taraboletti

D’Ascenzo

Borsotti

et al. 2002

The American Journal of Pathology

506

384

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Production of matrix-degrading proteases, particularly matrix metalloproteinases (MMPs), by endothelial cells is a critical event during angiogenesis, the process of vessel neoformation that occurs in normal and pathological conditions. MMPs are known to be highly regulated at the level of synthesis and activation, however, little is known about the regulation of MMP secretion by endothelial cells. We found that cultured human umbilical vein endothelial cells shed vesicles (300 to 600 nm) originating from localized areas of the cell plasma membrane, as revealed by ultrastructural analysis. Normal and reverse zymography, Western blot, and immunogold analyses of the vesicles showed two gelatinases, MMP-2 and MMP-9, in both the active and proenzyme forms, the MT1-MMP proenzyme located on the external side of the vesicle membrane and the two inhibitors TIMP-1 and TIMP-2. Serum and the angiogenic factors, fibroblast growth factor-2 and vascular endothelial growth factor, stimulated the shedding of MMPs as vesicle components. Shedding the vesicle was rapid, as it was already completed after 4 hours. Addition of shed vesicles to human umbilical vein endothelial cells resulted in autocrine stimulation of invasion through a layer of reconstituted basement membrane (Matrigel) and cord formation on Matrigel. We conclude that endothelial cells shed MMP-containing vesicles and this may be a mechanism for regulating focalized proteolytic activity vital to invasive and morphogenic events during angiogenesis. (Am J Pathol 2002, 160:673-680)

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Section: Discussionsupporting

confidence: 71%

Shedding of the Matrix Metalloproteinases MMP-2, MMP-9, and MT1-MMP as Membrane Vesicle-Associated Components by Endothelial Cells

Taraboletti

D’Ascenzo

Borsotti

et al. 2002

The American Journal of Pathology

506

384

View full text Add to dashboard Cite

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“…VEGF was reported to induce MMP-2 and MMP-9 secretion from RPE in vitro (Hoffmann et al, 2006). In addition, MMP activity was increased in microvascular endothelial cells exposed to VEGF (Lamoreaux et al, 1998). Although some studies suggest an overexpression or activation of MMPs in the pathology of neovascular AMD, others provide evidence that oxidants and toxins increase the formation of sub-RPE deposits and reduce the expression of MMP-2, suggesting that failed ECM turnover leads to deposits within Bruch's membrane and subsequent AMD pathology.…”

Section: Extracellular Matrix Proteolysis and Vegf-proteolytic Enzymementioning

confidence: 97%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

614

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…In vitro, endothelial cells (ECs) express a range of MMPs as well as TIMP-1, -2 and -3 [40][41][42] and it has been demonstrated that endothelial MMP expression and activity can be modulated by angiogenic factors. [43][44][45][46] Upregulated MMP expression has also been observed in blood vessels in vivo in several physiologic and pathologic conditions, indicating that MMPs are involved in the activity of the endothelium during these processes. As examples, these observations include increases in microvascular EC expression of MMP-1 during embryonic angiogenesis and vasculogenesis 47 and MMP-9 and -19 expression in ECs of the endothelium of rheumatoid arthritis synovium.…”

Section: Endogenous Inhibitors Of Metalloproteinasesmentioning

confidence: 99%

Metalloproteinases and their inhibitors in tumor angiogenesis

Handsley

Edwards

2005

Intl Journal of Cancer

260

211

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Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression. ' 2005 Wiley-Liss, Inc.Key words: metalloproteinase; tumor; angiogenesis; tissue inhibitor of metalloproteinases; protease; extracellular matrix Angiogenesis is an essential feature of several physiologic processes such as the developmental growth of organs, wound healing and the female reproductive cycle. 1 It is also particularly significant in cancer progression, being a crucial step in the transition of a tumor from a hyperplastic but contained in situ state to a malignant phenotype. 2,3 To allow its growth beyond a certain critical size, a solid avascular tumor must develop its own blood supply in order to meet its growing metabolic requirements. 1 Vascularization of a tumor also provides a route for dissemination of the tumor cells to different sites around the body.Although angiogenesis appears to be the primary form of tumor vascularization, the malignant cells of a tumor can gain access to a blood supply through other means, such as via tumor-induced vasculogenesis, in which bone marrow-derived precursor endothelial cells contribute to the formation of tumor vessels. 4,5 Vasculogenic mimicry is another form of vessel formation that has been reported in certain tumor types, such as aggressive human uveal melanomas, prostate and breast tumors. [6][7][8] In these cases, networks of tumor cell-lined vascular channels were identified within the tumors. Finally, vessel co-option, implemented by tumor cells as a temporary means of gaining access to a blood supply, involves the tumor cells growing around and thus co-opting existing host vessels to form an initially well-vascularized tumor. 9 This review will highlight new insigh...

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Vascular Endothelial Growth Factor Increases Release of Gelatinase A and Decreases Release of Tissue Inhibitor of Metalloproteinases by Microvascular Endothelial Cellsin Vitro

Cited by 253 publications

References 33 publications

Shedding of the Matrix Metalloproteinases MMP-2, MMP-9, and MT1-MMP as Membrane Vesicle-Associated Components by Endothelial Cells

Shedding of the Matrix Metalloproteinases MMP-2, MMP-9, and MT1-MMP as Membrane Vesicle-Associated Components by Endothelial Cells

Vascular endothelial growth factor in eye disease

Metalloproteinases and their inhibitors in tumor angiogenesis

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