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Endocrine Reviews
Copyright © 1997 by The Endocrine Society

Vol. 18, No. 1
Printed in U.S.A.

The Biology of Vascular Endothelial Growth Factor
NAPOLEONE FERRARA

AND

TERRI DAVIS-SMYTH

Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080

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IntroductionBiological Activities of VEGF
Organization of the VEGF Gene
Properties of the VEGF Isoforms
Regulation of VEGF Gene Expression
A. Hypoxia
B. Cytokines
C. Differentiation and transformation
The VEGF Receptors
A. Characterization and distribution of VEGF-binding sites
B. The Flt-1 and Flk-1/KDR tyrosine kinases
1. Binding characteristics
2. Signal transduction
3. Regulation
4.Structural requirements for ligand binding in
Flt-1 and Flk-1/KDR
5. VEGF determinants for binding Flt-1 and Flk1/KDR
VEGF-Related Molecules
Role of VEGF and Its Receptors in Physiological
Angiogenesis
A. Distribution of VEGF, Flk-1/KDR and Flt-1 mRNA
B. Analysis of Flk-1/KDR, Flt-1 and VEGF gene
knockouts
Role of VEGF in Pathological Angiogenesis
A. Tumor angiogenesis
1. Expression of VEGF inhuman tumors
2. Inhibition of VEGF action in vivo
B. Intraocular neovascular syndromes
C. Other pathological conditions
Therapeutic Applications of VEGF-Induced Angiogenesis
Perspectives

destructive events characteristic of these conditions. Leakage
and bleeding, followed by organization of the clot and fibrosis, may ultimately lead to retinal detachment or irreversible damage to themacula (5). Conversely, tumor-associated neovascularization, by establishing continuity with
the systemic circulation, allows the tumor cells to express
their critical growth advantage and also facilitates metastatic
spreading (3, 4). Accordingly, a correlation has been observed between density of microvessels in primary breast
carcinoma sections, nodal metastases, and survival (6 – 8).Similarly, a correlation has been reported between vascularity and invasive behavior in a variety of other tumors
(9 –12). These findings led several investigators to conclude
that the number of vessels in tumor sections is an independent predictor of outcome in cancer patients (9 –12).
The search for potential regulators of angiogenesis has
yielded numerous candidates: acidic fibroblast growth factor(aFGF), basic fibroblast growth factor (bFGF), transforming
growth factor- (TGF- ), TGF- , hepatocyte growth factor,
tumor necrosis factor- (TNF- ), angiogenin, interleukin-8
(IL-8), etc. (13, 14). Although these molecules are able to
promote angiogenesis, at least in certain model systems, it
has been difficult to correlate such activity with the physiological or pathological regulation ofblood vessel growth.
Work done by several laboratories over the last few years
has elucidated the pivotal role of vascular endothelial growth
factor (VEGF) in the regulation of normal and abnormal
angiogenesis (15). In particular, the recent finding that the
loss of even a single VEGF allele results in embryonic lethality points to an irreplaceable role played by this factor in
thedevelopment and differentiation of the vascular system
(16, 17). Furthermore, VEGF-induced angiogenesis has been
shown to result in a therapeutic effect in animal models of
coronary (18 –20) or limb (21–23) ischemia and, most recently,
in a human patient affected by critical leg ischemia (24).

I. Introduction

T

HE development of a vascular supply is a fundamental
requirement for organdevelopment and differentiation during embryogenesis (1, 2) as well as for wound healing
and reproductive functions in the adult (3, 4). Angiogenesis
is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration (AMD), tumors, rheumatoid arthritis, psoriasis, etc.
(3, 4). In the case of proliferative retinopathies and AMD, the
new...