VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase.
TL;DR: The data show that VEGF-A-induced FAK and PI3-kinase activation are required for migration of cells expressing VEGFR-2, via a pathway independent of direct interaction with the receptor.
About: This article is published in Experimental Cell Research.The article was published on 2001-02-01. It has received 131 citations till now. The article focuses on the topics: Vascular endothelial growth factor A & Vascular endothelial growth factor B.
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TL;DR: The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis.
Abstract: Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the migrating cells. It requires the activation of several signaling pathways that converge on cytoskeletal remodeling. Then, it follows a series of events in which the endothelial cells extend, contract, and throw their rear toward the front and progress forward. The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis.
1,297 citations
TL;DR: The current knowledge about the signal transduction properties of VEGF receptors is outlined, with focus on V EGF receptor-2, which appears to be involved in the regulation of angiogenesis.
920 citations
TL;DR: It is shown that VEGFR‐3 stimulation alone protects the lymphatic endothelial cells from serum deprivation‐induced apoptosis and induces their growth and migration, and defines the critical role of VEGF‐C/VEG FR‐3 signalling in the growth and survival of lymphatichelial cells.
Abstract: Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.
811 citations
TL;DR: VEGF plays a multifunctional role where it can also have autocrine pro‐survival effects and contribute to tumour cell chemoresistance and the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.
Abstract: Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.
669 citations
TL;DR: Vascular endothelial growth factors (VEGFs) constitute an expanding family of growth factors that have received considerable attention from the basic research community but also from clinically active scientists and pharmaceutical companies.
Abstract: The family of vascular endothelial growth factors (VEGFs) currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (PlGF). Several of these factors, notably VEGF-A, exist as different isoforms, which appear to have unique biological functions. The VEGF family proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. Neuropilins, heparan-sulfated proteoglycans, cadherins, and integrin alphavbeta3 serve as coreceptors for certain but not all VEGF proteins. Moreover, the angiogenic response to VEGF varies between different organs and is dependent on the genetic background of the animal. Inactivation of the genes for VEGF-A and VEGF receptor-2 leads to embryonal death due to the lack of endothelial cells. Inactivation of the gene encoding VEGF receptor-1 leads to an increased number of endothelial cells, which obstruct the vessel lumen. Inactivation of VEGF receptor-3 leads to abnormally organized vessels and cardiac failure. Although VEGF receptor-3 normally is expressed only on lymphatic endothelial cells, it is up-regulated on vascular as well as nonvascular tumors and appears to be involved in the regulation of angiogenesis. A large body of data, such as those on gene inactivation, indicate that VEGF receptor-1 exerts a negative regulatory effect on VEGF receptor-2, at least during embryogenesis. Recent data imply a positive regulatory role for VEGF receptor-1 in pathological angiogenesis. The VEGF proteins are in general poor mitogens, but binding of VEGF-A to VEGF receptor-2 leads to survival, migration, and differentiation of endothelial cells and mediation of vascular permeability. This review outlines the current knowledge about the signal transduction properties of VEGF receptors, with focus on VEGF receptor-2.
613 citations
Cites background from "VEGF-induced activation of phosphoi..."
...VEGF-A stimulates p85 subunit tyrosine phosphorylation and increased PI3K enzymatic activity in a variety of endothelial cells (164-168)--with the exception of sinusoidal endothelial cells (170)--through VEGFR-2 (150, 168, 190)....
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References
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TL;DR: The generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells is reported, indicating that FlK-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.
Abstract: The receptor tyrosine kinase Flk-1 (ref. 1) is believed to play a pivotal role in endothelial development. Expression of the Flk-1 receptor is restricted to endothelial cells and their embryonic precursors, and is complementary to that of its ligand, vascular endothelial growth factor (VEGF), which is an endothelial-specific mitogen. Highest levels of flk-1 expression are observed during embryonic vasculogenesis and angiogenesis, and during pathological processes associated with neovascularization, such as tumour angiogenesis. Because flk-1 expression can be detected in presumptive mesodermal yolk-sac blood-island progenitors as early as 7.0 days postcoitum, Flk-1 may mark the putative common embryonic endothelial and haematopoietic precursor, the haemangioblast, and thus may also be involved in early haematopoiesis. Here we report the generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells. Embryos homozygous for this mutation die in utero between 8.5 and 9.5 days post-coitum, as a result of an early defect in the development of haematopoietic and endothelial cells. Yolk-sac blood islands were absent at 7.5 days, organized blood vessels could not be observed in the embryo or yolk sac at any stage, and haematopoietic progenitors were severely reduced. These results indicate that Flk-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.
4,063 citations
TL;DR: It is proposed that rac and rho are essential components of signal transduction pathways linking growth factors to the organization of polymerized actin and that growth factors act through rac to stimulate this rho-dependent response.
3,294 citations
TL;DR: It is reported that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation, and it is suggested that the FlT-1 signalling pathway may regulate normal endothelium cell-cell or cell-matrix interactions during vascular development.
Abstract: The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the blood islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
2,723 citations
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: Surprisingly, the number of focal adhesions was increased in FAK-deficient cells, suggesting that FAK may be involved in the turnover of focalAdhesion contacts during cell migration.
Abstract: The intracellular protein tyrosine kinase FAK (focal adhesion kinase) was originally identified gy its high level of tyrosine phosphorylation in v-src-transformed cells. FAK is also highly phosphorylated during early development. In cultured cells it is localized to focal adhesion contacts and becomes phosphorylated and activated in response to integrin-mediated binding of cells to the extracellular matrix, suggesting an important role in cell adhesion and/or migration. We have generated FAK-deficient mice by gene targeting to examine the role of FAK during development. Mutant embryos displayed a general defect of mesoderm development, and cells from these embryos had reduced mobility in vitro. Surprisingly, the number of focal adhesions was increased in FAK-deficient cells, suggesting that FAK may be involved in the turnover of focal adhesion contacts during cell migration.
1,859 citations