Vascular endothelial growth factor A

About: Vascular endothelial growth factor A is a research topic. Over the lifetime, 15203 publications have been published within this topic receiving 1271498 citations. The topic is also known as: vascular endothelial growth factor A & vascular endothelial growth factor A165.

Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction

Abstract: Immune mechanisms have been implicated in placental dysfunction in patients with recurrent miscarriages and intrauterine growth restriction (IUGR), but the mediators are undefined. Here we show that complement activation, particularly C5a, is a required intermediary event in the pathogenesis of placental and fetal injury in an antibody-independent mouse model of spontaneous miscarriage and IUGR, and that complement activation causes dysregulation of the angiogenic factors required for normal placental development. Pregnancies complicated by miscarriage or growth restriction were characterized by inflammatory infiltrates in placentas, functional deficiency of free vascular endothelial growth factor (VEGF), elevated levels of soluble VEGF receptor 1 (sVEGFR-1, also known as sFlt-1; a potent anti-angiogenic molecule), and defective placental development. Inhibition of complement activation in vivo blocked the increase in sVEGFR-1 and rescued pregnancies. In vitro stimulation of monocytes with products of the complement cascade directly triggered release of sVEGFR-1, which sequesters VEGF. These studies provide the first evidence linking the complement system to angiogenic factor imbalance associated with placental dysfunction, and identify a new effector of immune-triggered pregnancy complications.

c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression

Abstract: c-Myc functions are necessary and sufficient for the entry of most cells into the DNA synthetic (S) phase of the cell cycle (Eilers et al. 1989; de Alboran et al. 2001; Trumpp et al. 2001), and MYC family genes are commonly activated in cancer. However, the precise mechanisms by which c-Myc promotes cell growth and transformation have not been resolved. Under physiological conditions c-myc expression is dependent on mitogens. This control is lost in cancer cells, resulting in elevated levels of c-Myc oncoprotein. In normal cells c-Myc activation triggers the apoptotic program (Askew et al. 1991; Evan et al. 1992), and thus c-Myc-induced transformation generally does not occur until there is a loss of function of apoptotic regulators. In particular, c-Myc triggers the ARF–Mdm2–p53 tumor suppressor pathway, and this prevents c-Myc-induced lymphomagenesis (Zindy et al. 1998; Eischen et al. 1999). However, c-Myc is also continuously required to maintain the transformed state (Felsher and Bishop 1999; Jain et al. 2002; Pelengaris et al. 2002), and disabling apoptosis alone is generally considered insufficient to promote tumorigenesis. Thus, Myc oncoproteins must provide other functions that initiate and/or sustain malignancy. Tumor progression and maintenance requires the development of an ample blood supply, which ensures the delivery of oxygen, nutrients, and growth factors. This requires the development of both immature and mature blood vessels. First, vasculogenesis, which is regulated by vascular endothelial growth factor (VEGF) and its receptors Flk-1 and Flt-1, establishes a primitive vascular network from newly differentiated endothelial cells that assemble into vascular tubes. Second, angiogenesis promotes the sprouting and remodeling of capillaries from these preexisting vessels (Risau 1997). This process requires the dissociation of pericytes from endothelial cells, and is regulated by interplay between angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) and signaling through their receptor Tie2 (Hanahan 1997). In the adult, angiogenesis is a tightly controlled process that regulates neovascularization during ovulation, placental development, and wound healing. Uncontrolled angiogenesis plays an important role during tumor growth (Hanahan and Folkman 1996), and the sprouting of new blood vessels into tumors suggests that angiogenesis is necessary for a successful malignancy. Angiogenesis is provoked early during tumor progression and occurs in part in response to environmental cues, in particular hypoxia, which regulates the expression of angiogenic factors critical for vasculogenesis and angiogenesis in tumors and during embryogenesis (Carmeliet et al. 1998; Iyer et al. 1998; Ryan et al. 1998). However, genetic changes in cancer may also flip the angiogenic switch. For example, in cell lines loss of p53 elevates VEGF levels (Volpert et al. 1997), whereas the oncogenes v-src, c-jun, and c-myc suppress the expression of the anti-angiogenic factor thrombospondin-1 (TSP-1; Mettouchi et al. 1994; Slack and Bornstein 1994; Tikhonenko et al. 1996). Furthermore, transgenic studies have shown that transformation induced by several oncoproteins, including c-Myc, is sufficient to induce an angiogenic response and the expression of VEGF (Kerbel et al. 1998; Pelengaris et al. 1999). However cause–effect relationships are difficult to establish, given that hypoxia accompanies tumor expansion in vivo. VEGF is a critical regulator of both vasculogenesis and angiogenesis (Hanahan 1997; Carmeliet and Collen 1999). Gene targeting in mice has shown that VEGF, Flk-1, and Flt-1 all have essential roles in early development, with lethality occurring between embryonic days 8.5 and 10.5 (E8.5 and E10.5; Fong et al. 1995; Shalaby et al. 1995; Carmeliet et al. 1996; Ferrara et al. 1996). Mouse embryos deficient in c-myc also die in utero at E10.5, and their lethality has been attributed to a delay in growth and cardiac and neural defects (Davis et al. 1993). Here we report that c-Myc deficiency results in profound defects in vasculogenesis, angiogenesis, and primitive erythropoiesis, and that these defects are associated with a failure in VEGF expression, and with improper expression of TSP-1, ANG-1, and ANG-2. The data support the model whereby c-Myc promotes tumorigenesis by functioning as a master regulator of cytokines necessary for growth, vasculogenesis, and angiogenesis.

G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models

Abstract: Recent studies suggest that tumor-associated CD11b+Gr1+ myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b+Gr1+ cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1α, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b+Gr1+ cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.

Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4

Abstract: The tyrosine kinases Flt4, Flt1, and Flk1 (or KDR) constitute a family of endothelial cell-specific receptors with seven immunoglobulin-like domains and a split kinase domain. Flt1 and Flk1 have been shown to play key roles in vascular development; these two receptors bind and are activated by vascular endothelial growth factor (VEGF). No ligand has been identified for Flt4, whose expression becomes restricted during development to the lymphatic endothelium. We have identified cDNA clones from a human glioma cell line that encode a secreted protein with 32% amino acid identity to VEGF. This protein, designated VEGF-related protein (VRP), specifically binds to the extracellular domain of Flt4, stimulates the tyrosine phosphorylation of Flt4 expressed in mammalian cells, and promotes the mitogenesis of human lung endothelial cells. VRP fails to bind appreciably to the extracellular domain of Flt1 or Flk1. The protein contains a C-terminal, cysteine-rich region of about 180 amino acids that is not found in VEGF. A 2.4-kb VRP mRNA is found in several human tissues including adult heart, placenta, ovary, and small intestine and in fetal lung and kidney.

A role for survivin in chemoresistance of endothelial cells mediated by VEGF.

Abstract: Although standard anticancer chemotherapeutic drugs have been designed to inhibit the survival or growth of rapidly dividing tumor cells, it is possible to enhance the efficacy of such drugs by targeting the proliferating host endothelial cells (ECs) of the tumor vasculature. A theoretical advantage of this strategy lies in the possibility of circumventing, or significantly delaying, acquired drug resistance driven by the genetic instability of tumor cells. Here, we show that both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor significantly reduce the pro-apoptotic potency of chemotherapy on both micro- and macrovascular ECs. This cytoprotection to drug toxicity was found to be phosphatidylinositol 3-kinase-dependent and could be recapitulated in the absence of VEGF by overexpressing the dominant-active form of the serine/threonine kinase protein kinase B/Akt. Downstream of phosphatidylinositol 3-kinase, we also show that survivin plays a pivotal role in VEGF-mediated EC protection by preserving the microtubule network. In this respect, its induction effectively protects ECs against chemotherapeutic damage, whereas overexpression of its dominant-interfering mutant (C84A) abrogates the protective effects of VEGF. Accordingly, the potency of VEGF as a chemoprotectant was more pronounced with drugs that interfere with microtubule dynamics than those that damage DNA. These studies implicate a role for survivin up-regulation as a novel mechanism of EC drug “resistance” and support the notion that angiogenic factors that induce the expression of survivin may act to shield tumor ECs from the apoptotic effects of chemotherapy. Thus, exploiting chemotherapeutic drugs as antiangiogenics is likely to be compromised by the high concentrations of proangiogenic survival/growth factors present in the tumor microenvironment; targeting EC survival pathways should improve the antiangiogenic efficacy of antineoplastic agents, particularly microtubule-inhibitor drugs.