Vascular Endothelial Growth Factor

The majority of studies have focused on sprouting angiogenesis, the proliferation and migration of endothelial cells from pre-existing blood vessels to form vascular structures. Sprouting angiogenesis appears to be mainly controlled by VEGF family members. First identified by Dvorak and colleagues due to its ability to induce vascular leaking and permeability in ascites, VEGF-A plays a central role in angiogenesis, inducing endothelial cell proliferation, migration, and survival.237 In addition, VEGF-A induces changes in endothelial cell morphology and motility, and upregulates expression of proteases, integrins, and a variety of mitogens. These changes facilitate endothelial cell migration and degradation of the basement membrane, necessary steps in the angiogenic process.

Homozygous or heterozygous deletion of VEGF-A results in embryonic lethality due to cardiovascular abnormalities and defects in vasculogenesis.238 VEGF-A is also required postnatally in physiological vasculogenic processes such as wound healing, ovulation and pregnancy.239 In common with other VEGF-A family members, VEGF-A occurs both in freely secreted and ECM-bound forms that can be released by the action of plasmin or MMPs. Binding to either VEGFR-1 (Flt-1) or VEGFR-2 (KDR or flk-1) is sufficient and necessary for the majority of VEGF's known functions.

Originally identified on endothelial cells, both VEGFR-1 and VEGFR-2 are also expressed within the hematopoietic compartment.241'242 In contrast, expression of a third family member, VEGFR-3 (Flt-4), is restricted to the lymphatic vasculature where it has been demonstrated to play a significant role in lymphangiogenesis.243 All three receptors possess an intrinsic intracellular kinase domain that is activated upon ligand binding. VEGF-A is bound by both VEGFR-1 and VEGFR-2 whereas receptor specific interactions are observed between other VEGF-A family members. Signaling through VEGFR-2 appears to mediate most of the actions of VEGF-A on endothelial cell biology. Similarly to the VEGF-A knockout phenotype, VEGFR-2 deficient mice die in utero due to defects in vascular development.244 In contrast, the precise role of VEGFR-1 in physiological and pathological angiogenesis remains to be fully clarified. Initial studies suggested that the normal physiological function of VEGFR-1 was to act as a negative regulator of VEGFR-2.245,246 More recent findings have indicated that VEGFR-1 has positive functions in certain cell types and can heterodimerize and transphosphorylate VEGFR-2. In particular, the positive actions of VEGFR-1 appear to be coopted in pathological conditions including tumor angiogenesis.239

Increased expression of VEGF-A within the tumor has been associated with disease progression, development of metastasis, and poor prognosis in multiple cancers.239,247,248 VEGF-A levels correlate with increased tumor vascularization and microvessel density, independent prognostic factors for breast carcinoma and NSCLC.239,249 Antagonistic antibodies and low molecular-weight inhibitors of VEGF-A signaling display antiangiogenic and antitumor effects in vivo, appearing to target mainly neovascularization rather than established vessels (see below). Despite the role of VEGF-A in physiological angiogenesis, several therapeutic entities have demonstrated clinical effectiveness while retaining an acceptable safety profile. The most advanced, Avastin, a VEGF-A-binding antibody, has been approved for treatment of patients with metastatic colorectal cancer.239,250,251

VEGF-A is one of the most potent inducers of vascular permeability known, an important function considering the extreme leakiness of tumor vessels. Increased intracellular trafficking (vesicovascular organelles), nitrous oxide (NO) production, and induction of endothelial fenestrations have been proposed as mechanisms by which VEGF-A induces increased permeability. Inhibition of VEGF-A signaling has been shown to be effective in preventing pathological conditions associated with increased permeability, such as pleural effusion and the formation of malignant ascites.239,252,253

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