Current biology of VEGF-B and VEGF-C

Abstract

Endothelial growth factors and their receptors may provide important therapeutic tools for the treatment of pathological conditions characterised by defective or aberrant angiogenesis. Vascular endothelial growth factor (VEGF) is pivotal for vasculogenesis and for angiogenesis in normal and pathological conditions. VEGF-B and VEGF-C provide this gene family with additional functions, for example, VEGF-C also regulates lymphangiogenesis.

Introduction

The inner lining of blood and lymphatic vessels, as well as the endocardium, consists of endothelial cells. The blood vasculature forms by two processes: vasculogenesis, the de novo formation of endothelial channels from differentiating angioblasts; and angiogenesis, the sprouting or splitting of capillaries from pre-existing vessels (reviewed in [1]). Polypeptide growth factors and their receptors are major components of the regulatory machinery that governs these processes. Two receptor tyrosine kinase families, the vascular endothelial growth factor (VEGF) receptors (VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4) and the angiopoietin receptors (Tie-1 and Tie-2/Tek) are the key players, being largely specific for endothelial cells. Other receptor families, such as the Eph family, also provide major contributions to vessel differentiation 2•, 3. Targeted gene disruptions in mice have verified their central importance in vessel growth, remodelling and maturation (4, 5, 6, 7, 8, 9••, reviewed in [10]).

Although the adult vasculature is normally quiescent, it can become activated to form new capillaries, for example, in wound healing and tumourigenesis. There is convincing evidence that tumours are angiogenesis dependent [11]. In the prevascular phase, a tumour’s volume rarely exceeds a few cubic millimetres and vessel density in invasive cancers (e.g. in prostate cancer) positively correlates with metastatic potential and prognosis [12]. During the so-called angiogenic switch in tumourigenesis, the balance between angiogenesis inhibitors (e.g. endostatin and thrombospondin-1) and angiogenesis inducers (e.g. VEGF) is shifted and rapid vessel ingrowth follows, supporting tumour expansion [11]. By default, endothelial cell turnover rates are low in resting vessels, whereas they are high in tumour vasculature. Angiogenesis is suggested to be a rate-limiting step in tumour development and angiogenesis inhibitors are thus attractive drugs for anticancer therapy. There are several benefits of directing drugs to the endothelium, including its general accessibility through the blood circulation and the absence of drug resistance in normal diploid and genetically stable endothelial cells, as opposed to the frequent development of resistance to cytotoxic therapy in genetically heterogeneous and unstable cancer cells 13, 14.

VEGF is a hypoxia-inducible endothelial cell mitogen. It stimulates endothelial cell migration and vessel permeability [15], and promotes survival of the newly formed vessels (reviewed in [16]). VEGF is crucial for embryonic development as targeted inactivation of even a single VEGF allele results in embryonic lethality 17, 18, and it is also required for survival in early postnatal life when the endothelium is still proliferating [19^•]. Although VEGF is highly specific for endothelial cells, it has become increasingly clear that it also elicits responses in non-endothelial cell types. For example, it is chemotactic for monocytes 20, 21 and can inhibit the maturation of dendritic cells [22]. VEGF receptors are also expressed in certain non-endothelial cell types in the testis and epididymis where overexpression of VEGF caused spermatogenic arrest, epithelial hyperplasia and infertility [23^•]. VEGF is also thought to be a regulator of bone formation via its effects on the osteoblasts and osteoclasts of growth plates 24, 25. The different splice variants of VEGF seem to differ in their function: in contrast to VEGF165, VEGF121 is unable to bind to the non-tyrosine kinase receptor neuropilin-1 [26], and in new-born gene-targeted mice, VEGF120 cannot compensate for the loss of the longer isoforms, leading to ischemic cardiomyopathy and death [27^•].

The family of VEGF-related molecules has recently grown and contains presently five mammalian members: VEGF; placenta growth factor (PlGF); VEGF-B; VEGF-C; and VEGF-D. The viral homologues, collectively called VEGF-E, are encoded by different strains of the Orf virus [28].