177
Anti-VEGF in the treatment
of AMD
17
Since the begining of the last century much attention
has been focused on tumour vascularization. Warren
Lewis
(1)
, in 1922, and Gordon Ide, in 1939
(2)
, had
already considered the hypothesis of synthesis of a vas-
cular growth factor by tumour cells. Synthesis of a vascu-
lar growth factor in the retina was proposed for the first
time in 1948
(3)
, in diabetic eyes by Isaac Michelson. In
the beginning of 1970, Folkman and his research group
demonstrated that tumour growth is directly related to
tumour vascularization, which, in turn, depends on the
expression of certain growth factors
(4)
.
2. Vascular endothelial growth – VEGF
VEGF was first identified in 1983 by Donald Senger and
Harold Dvorak’s group
(5)
, who identified the Tumour
Vascular Permeability Factor (VPF), which causes vascu-
lar hyperpermeability, in tumour cells from guinea pigs.
In 1989, 3 groups, including Ferrara et al, published
articles highlighting a molecule with pro-mitotic prop-
erties in endothelial cells. Ferrara et al. identified this
protein in bovines, having named it Vascular Endothelial
Growth Factor (VEGF), the term by which it has been
known since then
(6,7,8)
.
VEGF-A, a molecule involved in eye diseases such as
Age-related Macular Degeneration (AMD) and diabetic
retinopathy, is part of a family of genes that also includes
VEGF-B, C and D, and the viral homologue VEGF-E,
in addition to the Placental Growth Factor – PIGF.
VEGF-A, which has been extensively studied, is a dimeric
36-46 kd glycosylated protein with an N-terminal signal
sequence and a heparin-binding domain
(9,10)
.
Four different VEGF-A isoforms have been identi-
fied in humans with varying numbers of amino acids:
VEGF121, VEGF 165, VEGF 189 and VEGF 206.
They arise from alternative splicing of mRNA. The lon-
ger forms are matrix-bound and the shorter forms are
freely diffusible. VEGF 165 is the dominant isoform in
ocular neovascularization processes
(11)
.
2.1 VEGF receptors
Three VEGF receptors have been identified: VEGFR-1
(fms-like tyrosine kinase-1 or Flt-1), VEGFR-2 (kinase
insert domain-containing receptor or KDR) and
VEGFR-3 (fms-like tyrosine kinase-4 or Flt-4), which
is a receptor for VEGF-C and VEGF-D. VEGF-A binds
both to the R1 and R2 receptors.
VEGFR-2 is considered the main VEGF mediator in
endothelial cells. Its activation induces NO (nitric oxide)
production, cell membrane and cytoskeleton reorgani-
sation and proliferation and migration of endothelial
cells. It is also involved in the activation of the phospha-
tidylinositol 3-kinase (PI3)Akt pathway, which is a cru-
cial signal transduction pathway in the process leading to
endothelial cell survival induced by VEGF-A
(12)
.
2.2 Physiology of VEGF
VEGF-A is an important permeability inducer and is
about 50,000 times more potent than histamine. It is
also a potent mitogen in endothelial cells and may have
an important role in maturing of new blood vessels
through pericytes
(13)
.
VEGF-A is involved in physiological angiogen-
esis in adults, for example, in the female reproduction
cycle
(14)
. In addition, VEGF-A mRNA is expressed in
various healthy human adult tissues that do not show
1. Background
Authors:
Paulo Rosa, MD
1
João P Figueira, MD
2
1
Gama Pinto Ophthalmology Institute, Lisbon, Portugal.
2
Coimbra University Hospital - Coimbra, Portugal
