48
It is the balance of stimulators and inhibitors that tightly
controls the normally quiescent capillary vasculature.
When this balance is upset pathological angiogenesis de-
velops
(18)
.
During embryogenesis retinal vascularization begins in
the most superficial (or inner) retinal layers at the op-
tic nerve head, and radiates outwards from this central
point. It reaches the retinal periphery just before birth
(19)
.
The migration of large numbers of vascular precursor
cells (VPCs) from the optic disc is the first event in hu-
man retinal vascularization, apparent before 12 weeks
gestation
(20)
. They proliferate and differentiate to form
a primordial vascular bed centered on the optic disc.
Thus, vasculogenesis is responsible for the formation of
the primordial vessels of the inner (superficial) plexus in
the central human retina
(21)
. Formation of retinal vessels
via vasculogenesis appears independent of metabolic de-
mand and hypoxia-induced VEGF expression
(22)
.
Angiogenesis is responsible for the formation of the re-
maining retinal vessels, including increasing vascular
density in the central retina, vessel formation in the pe-
ripheral retina of the inner plexus, and formation of the
outer plexus and the radial peri-papillary capillaries
(22)
.
Formation of the outer plexus begins around the incipi-
ent fovea between 25 and 26 weeks of gestation, coin-
cident with the signals indicative of a functional visual
pathway and photoreceptor activity
(21)
. The timing and
topography of angiogenesis in the human retina supports
the “physiological hypoxia” model of retinal vascular for-
mation, in which angiogenesis is induced by a transient
but physiological level of hypoxia as a result of the in-
creased metabolic activity of retinal neurons as they dif-
ferentiate and become functional
(23)
.
Retinal anatomy is highly organized and vascular and
avascular compartments are strictly segregated in the
retina
(1).
The blood-retinal barriers, inner and outer, are
fundamental for the integrity of structure and optimiza-
tion of function in neuro-sensorial retina
(24)
.
Pathological retinal and choroidal angiogenesis generates
chaotically orientated and physiologically deficient ves-
sels that do not conform to neuronal histology, which
can lead to vision-threatening exudation and haemor-
rhage
(1)
.
Angiogenesis is a key aspect in many ocular pathologies
that are leading causes of blindness in the world, such
as neovascular age-related macular degeneration (AMD),
diabetic retinopathy, retinopathy of prematurity (ROP),
central retinal vein occlusion and other diseases associ-
ated with ischemia and neovascularization
(25)
.
Although angiogenesis is a highly complex and coordi-
nated process requiring multiple receptors and ligands
in endothelial cells, VEGF is a hypoxia-inducible cyto-
kine that appears to be a pivotal element required for
the process in a variety of normal and pathological cir-
cumstances
(3,10)
. Vascular endothelial growth factor is a
surrogate angiogenic marker, since it acts not only as a
mitogen, but also as a survival factor for endothelial cells
(EC)
(2)
. Furthermore, it is also involved in the stimula-
tion of the invasive and migration capacity of EC and in
the enhancement of vascular permeability
(10)
.
The diagnosis of age-related macular degeneration rests
on signs in the macula, irrespective of visual acuity
(26)
.
The stages of age-related macular degeneration are cat-
egorized as either early, in which visual symptoms are
inconspicuous, or late usually associated with severe loss
of vision
(27)
. Early AMD is characterized by the presence
of drusen and/or hyperpigmentations or small hypopig-
mentations
(26)
. Late AMD has “dry” and “wet” forms.
However, in the same patient we can find either the dry
form in one eye and the wet in the other eye, or the two
forms in the same eye. Moreover with time we can see
the conversion of wet in dry or dry becoming wet
(28)
.
Age-related changes that predispose to AMD occur in
the outer retina, more specifically in the region that in-
cludes the photoreceptors, the retinal pigment epithe-
lium (RPE), Bruch’s membrane and the choriocapillaris.
The aging-dependent alterations in the outer retina have
been already discussed in another chapter. AMD-related
visual loss is a complex process starting by the deposition
of debris in the outer retina
(29)
. The deposition of insolu-
ble material, the calcification and increase in thickness of
Bruch’s membrane, and a less fenestrated and thinner cho-
riocapillaris leads to photoreceptors/retinal pigment epithe-
lium hypoxia resulting in a stimulus for VEGF release
(28,30-32)
.
All the aging changes in outer retina compromise the
3. Angiogenesis during development
of retinal vasculature
4. Angiogenesis in retina and
choroidal pathologies
5. Angiogenesis and Age-related
Macular Degeneration
