The vascular endothelial growth factor family and its receptors

The vascular endothelial growth factor family

The VEGF family comprises six secreted glycoproteins that are designated VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF) (Fig. 1) [18], [19], [20]. The best characterized of the VEGF family members is VEGF-A (commonly referred to as VEGF, also known as vascular permeability factor), a 34- to 45-kD homodimeric glycoprotein. VEGF-A has a diverse range of angiogenic activities. In vivo, its expression was temporally and spatially associated with key events in physiologic

The vascular endothelial growth factor receptors

VEGF mediates its angiogenic effects by way of several different receptors. Two receptors were identified originally on various endothelial cells (ECs) and characterized as the specific tyrosine kinase receptors, VEGFR1 (fms-like tyrosine kinase [Flt-1]) and VEGFR2 (kinase-insert domain-containing receptor [KDR] and the murine homolog, fetal liver kinase-1 [Flk-1]) [33], [34]. These two receptors share 44% homology and possess a characteristic structure that consists of seven extracellular

Vascular endothelial growth factor 1

VEGFR1, first named “fms-like tyrosine kinase” (Flt-1) [36], [49], initially was believed to play a minor role in VEGF-mediated signal transduction [50]; however, recent animal studies suggested that VEGFR1 is critical in physiologic and developmental angiogenesis [51]. Some reports suggested that VEGFR1 functions as an inhibitor for VEGFR2-mediated cell proliferation but not cell migration [52], [53]. Although some studies suggested that the extracellular ligand binding domain is the important

Vascular endothelial growth factor receptor 2

VEGFR2 (KDR, Flk-1) mediates most of the downstream effects of VEGF in angiogenesis, including microvascular permeability [27], EC proliferation, invasion, migration, and survival [53], [64], [65]. The importance of VEGFR2 in vasculogenesis is demonstrated by the fact that hetero- and homozygous knockout mice died in utero of defects in blood island formation and vascular development [66]. VEGFR2-mediated proliferation of ECs is believed to involve activation of the ras/meiosis-specific kinase

Vascular endothelial growth factor receptor 3

VEGFR3 is a receptor tyrosine kinase that was cloned from a human leukemia cell line and human placenta [69], [70]. Initially, VEGFR3 is expressed throughout the embryonic vasculature; however, with maturation, its expression is limited to lymphatic ECs [37]. Homozygous VEGFR3 mutants undergo embryonic death at Day 10 to Day 12.5, with an underdeveloped yolk sac, poor perineural vasculature, and pericardial fluid accumulation [71]. Hereditary functional mutations of the VEGFR3 tyrosine kinase

Neuropilin-1 and neuropilin-2

Neuropilin (NRP)-1 was identified initially as a 130- to 140-kD cell-surface glycoprotein that served as a receptor for the semaphorin/collapsins, a large family of secreted and transmembrane proteins that serve as repulsive guidance signals in axonal and neuronal development [79], [80], [81]. During embryonic development, NRP-1 is expressed in the nervous, cardiovascular, and skeletal systems [79], [82], [83], whereas in adults it also is expressed in ECs, tumor cells, lung, heart, liver,

Summary of antivascular endothelial growth factor strategies

The recognition of VEGF and its family members as key players in the regulation of angiogenesis has led to the development of agents that inhibit its activity. Several anti-VEGF strategies have been developed, including neutralizing antibodies to VEGF or VEGFRs, soluble receptors/receptor hybrids, and tyrosine kinase inhibitors to VEGFRs [168], [169], [170], [171].

One of the earliest strategies that was used to inhibit VEGF activity involved the use of neutralizing antibodies to VEGF. In

Summary

The recognition that angiogenesis plays a critical role in a variety of pathologic conditions, including tumor growth, led to the discovery of several pro- and antiangiogenic factors and strategies. From its initial discovery as a potent vascular permeability factor to its current pluripotent angiogenic role, the VEGF family of ligands and receptors has been central to these discoveries. Continued progress has been made in the identification of new VEGF ligands and receptors as well as their

Acknowledgments

Supported, in part, by NIH grants T-32 09599 (A.A.P.) and CA74821 (L.M.E), The Lustgarten Foundation for Pancreatic Research (L.M.E), and the Lockton Fund Grant-Matching Program for Pancreatic Cancer Research (L.M.E). We thank Rita Hernandez from the Department of Surgical Oncology at M.D. Anderson Cancer Ceter for editorial assistance.