The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis

Senger, Donald R.; Perruzzi, Carole; Streit, Michael; Koteliansky, Victor; Fougerolles, Antonin R. de; Detmar, Michael

doi:10.1016/s0002-9440(10)64363-5

Cited by 313 publications

(253 citation statements)

References 43 publications

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“…Cell number was determined on days indicated with the CyQuant Cell Proliferation assay (Molecular Probes). Chemotaxis and haptotaxis assays were performed as described (19). For the woundscratch motility assay, cells were grown to confluence, and the monolayers were wounded identically with the narrow edge of a cell scraper (Falcon no.…”

Section: In Vitro Assays With Transduced Microvascular Ecs Measuremementioning

confidence: 99%

“…Neovascularization was assayed in vivo according to an established method (19)(20)(21) with important modification to include retroviral packaging cells as a constant source of retrovirus. Seven-week-old female athymic nude mice were injected s.c. on right and left flanks with 0.5 cc of 9 mg͞ml Matrigel (BD Bioscience) containing 1.5 ϫ 10 6 SK-MEL2 human melanoma cells transfected for stable expression of human VEGF 165 together with 1.5 ϫ 10 6 retroviral packaging cells, as indicated.…”

Section: Angiogenesis Assay and Analyses Of Blood Vessel Density Bloodmentioning

confidence: 99%

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Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Hoang

Whelan

Senger

2004

Proc. Natl. Acad. Sci. U.S.A.

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177

187

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The mechanisms that control organization of endothelial cells (ECs) into new blood vessels are poorly understood. We hypothesized that the GTPase Rho, which regulates cytoskeletal architecture, is important for EC organization during neovascularization. To test this hypothesis, we designed a highly versatile mouse skin model that used vascular endothelial growth factor-expressing cells together with packaging cells producing retroviruses encoding RhoA GTPase mutants. In this animal model, dominant negative N19RhoA selectively impaired assembly of ECs into new blood vessels; and, in contrast, active V14RhoA stimulated ECs to form blood vessels with functional lumens. In vitro, dominant negative N19RhoA reduced EC actin stress fibers and prevented ECs from contracting and reorganizing into precapillary cords within collagen gels. In contrast, active V14RhoA promoted EC stress fiber formation, contractility, and organization into cords. Neither N19RhoA nor V14RhoA significantly affected EC proliferation or migration in vitro; and, similarly, neither mutant significantly affected EC density during angiogenesis in vivo. Thus, these studies identify a critical and selective role for Rho activity in regulating EC assembly into new blood vessels, and they identify both negative and positive manipulation of Rho activity, respectively, as strategies for suppressing or promoting the organizational stages of neovascularization.

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Section: In Vitro Assays With Transduced Microvascular Ecs Measuremementioning

confidence: 99%

Section: Angiogenesis Assay and Analyses Of Blood Vessel Density Bloodmentioning

confidence: 99%

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Hoang

Whelan

Senger

2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

177

187

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“…Antagonism of avb3 does not prevent responsiveness to VEGF among collagen-adherent cells. 57 However, among endothelial cells bound to fibrin, antagonism of integrin avb3 influences with both adhesion and signaling events. 55 The requirement for a particular integrin to promote signaling events in response to a growth factor is therefore likely to be influenced by the ECM composition of the local microenvironment.…”

Section: General Signaling Events Initiated By Integrinsmentioning

confidence: 99%

“…94 The activation of MAPKs has been linked to integrin-dependent survival in a number of cases. 40,51,57,67,95 Nevertheless, the activation of PI3K/Akt may be more important at regulating cell viability in the presence of unligated integrins, since constitutively active Akt prevents apoptosis induced via death receptors [96][97][98][99][100] or active forms of caspase 8. 101 It is possible that Akt may phosphorylate a peptide loop on caspase 8 proximal to the catalytic site.…”

Section: Signaling Cascades and The Integrin Rheostatmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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“…Several studies have reported the association of the integrin signaling with functions of vascular endothelial cells. For example, Senger et al (47) showed that Itga1/b1 and Itga2/b1 provide critical support for VEGF signaling and endothelial cell migration and tumor angiogenesis. Compared with these studies, however, our proteomic data provide a comprehensive proteome resource that can be used in various studies of retinal vascular hyperpermeability and also the network model (Fig.…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bae

Chae

et al. 2016

Molecular & Cellular Proteomics

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Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the ␤2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the ␤2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents. Molecular & Cellular Proteomics

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The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis

Cited by 313 publications

References 43 publications

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Integrins as a distinct subtype of dependence receptors

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

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