VEGFA Receptors and Signaling Pathways

VEGF-A mediates its effects primarily by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1) (Figure 2). Cultured endothelial cells have approximately 3,000 copies of VEGFR-1, which binds VEGF-A165 with a Kd of approximately 10pM; they have more numerous copies of VEGFR-2, which binds VEGF-A165 with somewhat lower affinity (Kd of 75 to 125 pM). A truncated soluble form of VEGFR-1 (sFlt) that results from alternative splicing is found in serum and retains VEGF-A binding activity. sFlt has recently been implicated in pre-eclampsia, a serious complication of pregnancy. A third, nonkinase receptor, neuropilin (NRP-1) has been found; NRP-1 potentiates VEGF-A164/5's binding to VEGFR-2. Neuropilin had been known as a receptor for the semaphorin/collapsin family of neuronal guidance mediators, and it is also expressed widely on nonendothelial cells. VEGF-A164/5, B, E, and PlGF bind to NRP-1, but VEGF-A120/1 does not (Figure 2); this inability may explain some of the abnormalities in mice engineered to express only the VEGF-A120 isoform. Two other members of the VPF/VEGF family (VEGF-B and both isoforms of PlGF) bind to VEGFR-1, whereas VEGFs C, D, and E bind to VEGFR-2.

Mice null for any of the three VEGF-A receptors are embryonic lethals. VEGFR-1 null mice die at day 8.5 to 9.0 as a result of vessel obstruction by an overgrowth of endothelial cells. VEGFR-2 knockout mice die at a similar stage of development because of failure of endothelial and

Figure 2 Binding Specificities of the VPF/VEGF Ligand Family Members and Their Receptors. VEGFR-1 and VEGFR-2 are expressed on vascular endothelial cells as well as on some other cell types; VEGR-3 is expressed on lymphatic endothelium in the adult but also on some tumor vessels. NRP-1 is expressed on vascular endothelium, neurons, and some tumor cells (see text for further details). [Republished with permission from H. Dvorak (2002), Journal of Clinical Oncology 20, 4368.] (see color insert)

Figure 2 Binding Specificities of the VPF/VEGF Ligand Family Members and Their Receptors. VEGFR-1 and VEGFR-2 are expressed on vascular endothelial cells as well as on some other cell types; VEGR-3 is expressed on lymphatic endothelium in the adult but also on some tumor vessels. NRP-1 is expressed on vascular endothelium, neurons, and some tumor cells (see text for further details). [Republished with permission from H. Dvorak (2002), Journal of Clinical Oncology 20, 4368.] (see color insert)

hematopoietic precursor cells. NRP-1 null mice also die from a failure of vascular development.

VEGFR-1 and VEGFR-2 are widely expressed on normal vascular endothelium, and expression is upregulated in tumor blood vessel endothelium and in that of other examples of pathological angiogenesis induced by VEGF-A. The mechanisms responsible for receptor overexpression are not yet fully understood, but hypoxia, which stimulates VEGF-A expression (see following discussion), may also upregu-late VEGF receptor expression.

Recent reports indicate that VEGF-A receptors may also be expressed on tumor cells, raising the possibility of an autocrine loop that might stimulate tumor cell growth and migration. VEGFR-1 is additionally expressed on a population of hematopoietic stem cells and myeloid progenitors as well as on monocytes/macrophages, spermatogenic and Leydig cells, uterine smooth muscle cells, and osteoclasts. VEGFR-1 has an important role in mediating hematopoietic cell development and recruitment, particularly that of mono-cytes, and mediates VEGF-A-induced monocyte (but not endothelial cell) motility. As noted previously, VEGFR-1 null embryos die as a result of an overgrowth of endothelial cells, implying, along with data from cultured endothelial cells, that this receptor exerts a negative regulatory effect on the VEGF-A activities governed by VEGFR-2 signaling. VEGFR-2 is expressed on bone marrow endothelial cell progenitors, megakaryocytes, uterine smooth muscle cells, and lymphatic endothelium.

Although binding to VEGF-A with high affinity, VEGFR-1 induces only minimal stimulation of kinase activity in vascular endothelium; as a result, downstream signaling pathways have had to be worked out in endothelial cells that were engineered to overexpress this receptor. Much more is known about the signaling pathways initiated through VEGFR-2 (Figure 3). Upon binding to VEGFR-2, VEGF-A initiates a cascade of events that begins with receptor dimerization and autophosphorylation followed by phosphorylation of numerous downstream proteins. Very recently, G proteins have been implicated in VEGF-A signaling. Most of the biological activities mediated by VEGF-A on endothelial cells (e.g., proliferation, migration, vascular permeability, antiapoptosis) are mediated through VEGFR-2 signaling. VEGFR-2 also has an important role in the development of endothelial cell precursors present in the bone marrow and circulating in blood.

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