The VEGF XXXb isoforms share approximately 94–98% homology with the corresponding VEGF XXX isoforms and have the same length. Recently, discovery of the so called “VEGF XXXb isoforms” has sparked new interest in the molecular events that regulate VEGF expression (for review, see Ladomery et al., 2007). Exons 1 – 5 span the receptor binding domain, while exons 6 and 7 span the heparin binding domain. B) Variants of VEGF-A are formed by alternative splicing. Our understanding of the relative expression of the different VEGF isoforms under normal or pathological conditions and the molecular regulators of VEGF alternative splicing is relatively limited.Ī) Associations of various VEGF isoforms with VEGF receptors and co-receptors and basic receptor structure. Moreover, plasmin and various metalloproteinases can cleave VEGF 165, resulting in an N-terminal 113-amino acid peptide that is non-heparin-binding, but retains its bioactivity ( Keyt et al., 1996 Ferrara et al., 2003).
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Investigations in mice genetically engineered to express less than the full complement of splice variants confirm that the relative solubility of VEGF splice variants strongly affects their specific bioactivities ( Takahashi and Shibuya, 2005). VEGF 165 binds heparin with less affinity, but also can be associated with the matrix, and VEGF 121 lacks heparin-binding capacity, rendering it highly soluble. VEGF 206 and VEGF 189 bind very tightly to heparin and, thus, remain sequestered in the extracellular matrix. The solubility of these splice variants (collectively referred to as VEGF XXX) is dependent on heparin binding affinity. In humans, these include the relatively abundant VEGF 121, VEGF 165, VEGF 189 and VEGF 206, and several less abundant forms ( Fig. Alternative splicing results in several VEGF variants. In mammals, the VEGF family consists of seven members: VEGF-A (typically, and hereafter, referred to as VEGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and PlGF (placental growth factor) ( Fig. It is essential for angiogenesis during development the deletion of a single allele arrests angiogenesis and causes embryonic lethality ( Ferrara et al., 1996). Vascular endothelial growth factor (VEGF), a dimeric glycoprotein of approximately 40 kDa, is a potent, endothelial cell mitogen that stimulates proliferation, migration and tube formation leading to angiogenic growth of new blood vessels. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.ġ.1 Vascular Endothelial Growth Factor (VEGF) This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions.
Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries.
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