Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies

Abstract

The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.

Keywords: VEGF; VEGF receptor; anti-angiogenic therapy; neuronal degeneration; pro-angiogenic therapy; tumor angiogenesis.

Figure 1.

The VEGF and VEGFR system. VEGF-A and its receptors, VEGFR-1 and VEGFR-2, play a major role in vasculogenesis and angiogenesis. In addition, sFlt-1, a soluble form of VEGFR-1, is expressed in various cells such as trophoblasts and negatively regulates angiogenesis.

Figure 2.

Unique activation of VEGFRs by VEGF-E and Trimeresurus flavoviridis svVEGF. VEGF-E encoded in the Orf viral genome binds to and activates only VEGFR-2, inducing well-organized blood vessels. T. flavoviridis svVEGF stimulates vascular permeability by activation of VEGFRs in a specific manner.

Figure 3.

A possible response of tumor cells to anti-angiogenic therapy: a model. A direct suppression of tumor angiogenesis and “vascular normalization” results in the suppression of tumor growth. However, after long-term therapy, tumor cells under hypoxia and low nutrition double stress acquire a resistant phenotype.

Figure 4.

A pro-angiogenic therapy using the VEGF-VEGFR system. Recent studies suggest that sensory neurons express VEGFR-1 and motoneurons express VEGFR-2. These receptors are biologically functional, and therefore, an appropriate ligand, such as VEGF-E, can be used for pro-angiogenic therapy as well as for neuron protection therapy.