Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148
TL;DR: Overall the data indicate that VE-cadherin–β-catenin complex participates in contact inhibition of VEGF signaling, which is required to restrain growth factor signaling.
Abstract: Confluent endothelial cells respond poorly to the proliferative signals of VEGF. Comparing isogenic endothelial cells differing for vascular endothelial cadherin (VE-cadherin) expression only, we found that the presence of this protein attenuates VEGF-induced VEGF receptor (VEGFR) 2 phosphorylation in tyrosine, p44/p42 MAP kinase phosphorylation, and cell proliferation. VE-cadherin truncated in β-catenin but not p120 binding domain is unable to associate with VEGFR-2 and to induce its inactivation. β-Catenin–null endothelial cells are not contact inhibited by VE-cadherin and are still responsive to VEGF, indicating that this protein is required to restrain growth factor signaling. A dominant-negative mutant of high cell density–enhanced PTP 1 (DEP-1)//CD148 as well as reduction of its expression by RNA interference partially restore VEGFR-2 phosphorylation and MAP kinase activation. Overall the data indicate that VE-cadherin–β-catenin complex participates in contact inhibition of VEGF signaling. Upon stimulation with VEGF, VEGFR-2 associates with the complex and concentrates at cell–cell contacts, where it may be inactivated by junctional phosphatases such as DEP-1. In sparse cells or in VE-cadherin–null cells, this phenomenon cannot occur and the receptor is fully activated by the growth factor.
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TL;DR: Evidence is assembled of possible interrelations between Wnt and other growth factor signaling, β-catenin functions, and cadherin-mediated adhesion in tissue differentiation.
Abstract: The specification and proper arrangements of new cell types during tissue differentiation require the coordinated regulation of gene expression and precise interactions between neighboring cells. Of the many growth factors involved in these events, Wnts are particularly interesting regulators, because a key component of their signaling pathway, β-catenin, also functions as a component of the cadherin complex, which controls cell-cell adhesion and influences cell migration. Here, we assemble evidence of possible interrelations between Wnt and other growth factor signaling, β-catenin functions, and cadherin-mediated adhesion.
2,412 citations
TL;DR: In this paper, the authors investigated the pathway upstream of integrin activation and found that PECAM-1 and VEGFR2 are sufficient to confer responsiveness to flow in heterologous cells.
Abstract: Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.
1,387 citations
TL;DR: How the molecular architectures and interactions may represent a mechanistic basis for the function and regulation of junctions, focusing on junction assembly and permeability regulation, is emphasized.
Abstract: Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight junctions, adherens junctions, and gap junctions. The expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs. Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells. Tight junctions serve the major functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes. In addition, they are required for a correct organization of new vessels in angiogenesis. Extensive research in the past decade has identified several molecular components of the tight and adherens junctions, including integral membrane and intracellular proteins. These proteins interact both among themselves and with other molecules. Here, we review the individual molecules of junctions and their complex network of interactions. We also emphasize how the molecular architectures and interactions may represent a mechanistic basis for the function and regulation of junctions, focusing on junction assembly and permeability regulation. Finally, we analyze in vivo studies and highlight information that specifically relates to the role of junctions in vascular endothelial cells.
1,185 citations
TL;DR: Junctional structures maintain the integrity of the endothelium and might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation.
Abstract: Junctional structures maintain the integrity of the endothelium Recent studies have shown that, as well as promoting cell–cell adhesion, junctions might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation Moreover, modifications of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis
1,157 citations
TL;DR: A clear understanding of the tight and multi-level regulation of VEGFR2 signalling is key to successful therapeutic suppression or stimulation of vascular growth.
Abstract: Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.
958 citations
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TL;DR: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases and integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases, but owing to several unanswered questions, caution is needed.
Abstract: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases But owing to several unanswered questions, caution is needed
8,561 citations
"Contact inhibition of VEGF-induced ..." refers background in this paper
...VEGF plays an important role in the formation of new vessels during embryogenesis and in proliferative diseases in the adult (Ferrara and Alitalo, 1999; Carmeliet and Jain, 2000; Dor et al., 2002)....
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TL;DR: In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
Abstract: The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by -catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
3,277 citations
"Contact inhibition of VEGF-induced ..." refers background in this paper
...-Catenin up-regulates transcription of cyclin D1 and c-myc (Polakis, 2000; Gottardi and Gumbiner, 2001; van de Wetering et al., 2002; Conacci-Sorrell et al., 2002), and inhibition of its activity would limit growth....
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...-Catenin is considered an oncogene and, in tumor cells, can induce transcription of genes important in cell cycle regulation (Polakis, 2000; Conacci-Sorrell et al., 2002; van de Wetering et al., 2002)....
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TL;DR: The Flk-1/KDR receptor and the PI3-kinase/Akt signal transduction pathway are identified as crucial elements in the processes leading to endothelial cell survival induced by VEGF, and inhibition of apoptosis may represent a major aspect of the regulatory activity of V EGF on the vascular endothelium.
1,988 citations
TL;DR: Targeted inactivation or truncation of the beta-catenin-binding cytosolic domain of the VE-cadherin gene was found to affect assembly of endothelial cells in vascular plexi, but to impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation.
1,320 citations
"Contact inhibition of VEGF-induced ..." refers background in this paper
...However, in previous work (Carmeliet et al., 1999), we observed that, instead, expression of VE-cadherin reinforced VEGFR-2 activation of PI3 kinase, accompanied by a marked decrease in endothelial cell sensitivity to apoptotic stimuli....
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...VE-cadherin forms a complex with VEGFR-2 In previous work (Carmeliet et al., 1999), we found that VEcadherin can be coimmunoprecipitated with VEGFR-2....
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...The absence of VE-cadherin at junctions, as in VE-cadherin–null animals (Carmeliet et al., 1999) or in animals treated with blocking antibodies (Corada et al....
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...We published previously that VE-cadherin can form a complex with VEGFR-2 upon activation of the cells with VEGF, and this paralleled VEGFR-2 localization at intercellular junctions (Carmeliet et al., 1999; Shay-Salit et al., 2002; Zanetti et al., 2002)....
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...VE-cadherin forms a complex with VEGFR-2 In previous work (Carmeliet et al., 1999), we found that VEcadherin can be coimmunoprecipitated with VEGFR-2....
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TL;DR: Current evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis, and both therapeuticAngiogenesis using recombinant V EGF or VEGFs gene transfer and inhibition of VEGf-mediated pathological angiogenic are being pursued.
Abstract: Vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. Recent evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis. Furthermore, VEGF is required for the cyclical blood vessel proliferation in the female reproductive tract and for longitudinal bone growth and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of many tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued.
1,206 citations
"Contact inhibition of VEGF-induced ..." refers background in this paper
...VE-cadherin expression inhibits VEGFR-2 phosphorylation VEGFR-2 plays a major role in the growth factor–induced endothelial cell proliferation (Ferrara, 1999) and p44/42 MAP...
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...VE-cadherin expression inhibits VEGFR-2 phosphorylation VEGFR-2 plays a major role in the growth factor–induced endothelial cell proliferation (Ferrara, 1999) and p44/42 MAP Th e Jo ur na l o f C el l B io lo gy VE-cadherin and VEGF | Lampugnani et al. 795 kinase activation (Takahashi et al.,…...
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