Vascular Endothelial Growth Factors

VEGF-A, originally identified and isolated on the basis of its ability to stimulate permeability in blood vessels, is a critical factor for normal vascular development and angiogenesis (34). VEGF-A is a member of the PDGF family of dimeric cysteine-knot growth factors that also includes the other VEGF members: VEGF-B, VEGF-C, VEGF-D, and placental growth factor (35). Multiple forms of VEGF-A are produced through alternate mRNA splicing to generate at least four iso-forms in humans: VEGF121, VEGF165, VEGF189, and VEGF206 (36). All of the major VEGF-A isoforms are secreted from cells as homodimers, and all except VEGF121 contain a consensus heparin-binding domain in the C-terminal domain that is comprised of 15 basic amino acids. The binding of some VEGF-A isoforms to heparin is believed to reflect important interactions with HS pro-teoglycans within the ECM. VEGF-A binds to major receptor tyrosine kinases VEGFR-1 (also known as Flt-1) and VEGFR-2 (also known as Flk-1 and KDR) (34,37,38), and to the non-tyrosine kinase transmembrane proteins neuropilin-1 and neuropilin-2 (39). In endothelial cells, VEGF-A is believed to transduce its biological activities mainly through VEGFR-2. However, many open questions remain regarding the role of other VEGF receptors and binding sites on endo-thelial and other cell types. For example, there is evidence that VEGFR-1 acts as a decoy receptor that sequesters VEGF and attenuates the activity of VEGFR-2 (37,40), and there is evidence that VEGFR-1 signals directly in response to VEGF-A to stimulate monocyte migration (41). Clearly, VEGF-A is critical to many aspects of tissue growth and repair, and the activity of this growth factor is controlled in a complex manner. The complexity is even more daunting when one considers the potential roles of the various co-receptors on the cell surface and ECM-binding sites, which not only interact with VEGF-A but also with VEGF receptors. Thus, it is clear that useful pharmacodynamic models will need to consider a wide array of factors present on and near the target cell surface.

VEGF-A expression is regulated at the transcriptional, translational, and posttranslational levels. Of particular interest is the regulation of VEGF expression by hypoxia-induced factor (HIF), a transcription factor that is stabilized at low oxygen pressure (42). Through this mechanism, increased VEGF-A expression is thought to drive the development of new blood vessels to hypoxic tissue sites. It is also interesting to note that the deposition of VEGF-A within the ECM might additionally be modulated by the local tissue environment. Indeed,

VEGF-A binding to HS and fibronectin, two major ECM components, is enhanced at acidic pH, indicating a possible biological mechanism for VEGF-A deposition at sites of tissue injury where local hypoxia would lead to acidification of the extracellular space (43-45). This pH-regulated growth factor deposition might, in turn, be co-opted for the development of regulated growth factor release systems. For example, incorporation of VEGF-A into synthetic ECM-like devices at low pH could provide a local depot of growth factor that would progressively release VEGF-A as the tissue becomes vascularized and the local pH returns to neutrality. Thus, the regulation of VEGF-A by interactions with the ECM will be a critical consideration in the design of approaches to deliver VEGF-A in a therapeutically effective manner.

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