178
In clinical practice, observed blood VEGF levels are
increased in AMDpatients
(24)
. Many studies have revealed
VEGF overexpression in neovascular membranes during
autopsy procedures or after surgical extraction
(25,26)
.
Since 1996, immunohistochemistry studies of frozen sec-
tions of neovascular membranes have shown significant
VEGF levels in highly vascularized regions, although
lower immunoreactivity has been observed in fibrotic
membrane regions
(28,29)
. Drusens and basal linear depos-
its have also been associated with high VEGF levels
(30)
.
Therefore, vascular endothelial growth factor A
(VEGF-A) regulates angiogenesis and vascular perme-
ability in the eye, both in physiological and pathologi-
cal processes. This growth factor selectively influences
endothelial cell growth, being particularly responsible
for increased vascular permeability. It also plays a role in
the survival of many cells. Inhibition of neovasculariza-
tion – the cause of exudative or neovascular AMD – was
the basis of some disease-modifying therapies, since anti-
VEGFs may delay or even halt disease progression. The
vascular endothelial growth factor is a secreted protein
that induces angiogenesis and increases vascular perme-
ability and inflammation, which appear to contribute
to neovascular AMD progression. Naturally, VEGF is
the target of investigational drugs for the treatment of
AMD
(31,32)
.
It is possible to inhibit every step of the angiogenesis cas-
cade induced by VEGF: VEGF synthesis may be inhib-
ited by inhibiting the synthesis of the corresponding
mRNA or by inhibiting transcription
(33)
. The effect of
VEGF may also be directly inhibited , by inhibiting pro-
tein action. This is the mechanism used in anti-VEGF
therapies
(34,35)
. Angiogenesis may also be inhibited after
VEGF binding, as occurs with anecortave acetate and
squalamine lactate
(36-38)
.
Treatment of AMD with anti-VEGFs is thus considered
to be a turning point since its emergence has allowed
a more direct approach to choroidal neovasculariza-
tion and its selective inhibition. Therefore, anti-VEGF
treatments offer new hope to thousands of neovascular
AMD patients, a disease that used to be understood as an
untreatable condition associated with ageing before the
emergence of anti-VEGF drugs.
These drugs are particularly effective in the early stages
of the disease, when newly formed blood vessels are less
mature: inhibition of their growth allows photoreceptors
to remain viable, as well as reducing the risk of central
fibrosis and delaying progressive loss of vision.
Three drugs in this class are currently used in the treat-
ment of AMD: pegaptanib (Macugen®), ranibizumab
angiogenesis, such as the epithelium of the choroid
plexus in the brain, the glomerular epithelium in the
kidney, the gastrointestinal mucosa and hair follicles
(15)
.
It has been suggested that VEGF-A maintains the integ-
rity of endothelial cells via anti-apoptotic signalling
(15)
.
VEGF-A has been recognised as an important neuropro-
tectant in the central nervous system. VEGF-A exposure
resulted in a dose-dependent reduction in retinal neu-
ronal apoptosis
(16)
. Although mechanistic studies have
suggested that VEGF-induced volumetric blood flow
to the retina may be partially responsible for neuropro-
tection, ex vivo retinal cultures have revealed a direct
neuroprotective effect for VEGF-A. VEGF receptor-2
expression has been detected in several neuronal cell lay-
ers of the retina, and functional analyses have shown that
VEGFR-2 is involved in retinal neuroprotection
(16)
.
It has been shown that VEGF-A is secreted by Retinal
Pigment Epithelial (RPE) cells, on their basal side,
i.e. the side adjacent to the choriocapillaris, and the 3
VEGFRs are expressed in choriocapillaris endothelial
cells, on the side facing retinal pigment epithelial cells. It
has long been known that loss of RPE cells in the human
eye causes atrophy of the choriocapillaris. These findings
are consistent with a role of VEGF-A secreted by RPE
cells as a permeability/survival factor for quiescent cho-
riocapillaris endothelium
(17)
.
Since VEGF is highly regulated by hypoxia, a feedback
mechanism must exist in these epithelia to promote
physiological formation of new blood vessels when tis-
sue oxygenation is low. Unbalances in this mechanism
may cause serious diseases, such as Exudative Age-related
Macular Degeneration (AMD)
(15)
.
2.3 VEGF and pathology
The predominant role of VEGF-A in the development
of pathological angiogenesis, such as that occurring in
tumours and ischaemic and inflammatory processes was
widely demonstrated in the last decade
(18)
.
In hypoxic states, VEGF is secreted by RPE cells
(19)
. This
factor induces endothelial cell proliferation and increases
vascular permeability. It has been shown in several models
that VEGF-A is required and sufficient for development
of new blood vessels in the retina and the iris. As already
mentioned, VEGF-A has been identified as a primordial
factor in the neovascular response induced by retinal
ischaemia. Therefore, VEGF-A levels are increased in the
vitreous and retina of patients with neovascularization
secondary to proliferative diabetic retinopathy, venous
occlusion or retinopathy of prematurity
(20-23)
.
