49
Angiogenesis
nutrition of photoreceptors and RPE and create a fa-
vourable ambiance for the development of choroidal
neovascularization. However other factors – genetic and
environmental
(33,34)
– are also important, but their roles
in the development of CNV is discussed in other chap-
ters of this book.
In general terms there are two basic CNV growth pat-
terns, based on the anatomical position of the abnormal
vessels with respect to the RPE monolayer, which are
related to the Gass classification of choroidal neovascu-
larization
(35,36)
. Type 1 signifies CNV located in the plane
between the RPE and Bruch’s membrane and type 2 neo-
vascularization means that the vessels have penetrated the
RPE layer to proliferate in the subneurosensory space
(35)
.
In type 1 growth pattern after breaking through Bruch’s
membrane, tufts of CNV extend laterally under the RPE
in a horizontal fashion facilitated by the natural cleav-
age plane between basal laminar deposits and a lipid rich
Bruch’s membrane. This growth pattern recapitulates the
choriocapillaris and can provide some nutrients and oxy-
gen to an ischemic RPE/outer retina
(36,37)
.
The type 2 growth pattern occurs usually with one or
few ingrowth sites with vascular leakage under the RPE/
outer retina, leading to acute visual symptoms
(36)
.
Recently, Yannuzzi proposed a type 3 neovascularization,
for retinal angiomatous proliferation (RAP), indicating
proliferating vessels within or below the retina itself
(38)
.
This mixed neovascularization, with a presumed dual
origin, may have intraretinal neovascularization driven
by angiogenic cytokines from Müller cells, endothelial
cells, pericytes, and retinal glial cells, and CNV driven by
cytokines from the RPE
(38)
. There is hypothetically neo-
vascularization extending anteriorly from the choroid in
conjunction with retinal neovascularization progressing
posteriorly, with both circulations destined to anastomose.
The reason that growth patterns vary according to disease
and individual may be related to genetic predispositions,
environmental mechanisms, variations in composition
and anatomy of Bruch’s membrane, cytokine distribu-
tion, or other causes
(36)
.
During the dynamic process of development of CNV
there is a balance of angiogenesis promoters and inhibi-
tors. In the initiation stage, the RPE and photorecep-
tors produce VEGF
(39)
. There is also production by RPE
of Interleukin-8 (IL-8) and Monocyte Chemoattractant
Protein-1 (MCP), which attract monocytes from the
choriocapillaris along the outer surface of Bruch’s mem-
brane
(40)
. The macrophages tend to concentrate around
sites of vascular ingrowth through the Bruch’s membrane
and express Tumor Necrosis Factor-
α
(TNF-
α
) and In-
terleukin-1 (IL-1), which up-regulate complement fac-
tor-B, activate the complement alternative pathway in
the subretinal space, and stimulates RPE cells to produce
more VEGF
(40,41)
.
After initiation, CNV grows to a certain size and pro-
gresses through the tissue planes by the action of Matrix
Metalloproteinases (MMP) produced by EC and macro-
phages
(42)
. During this stage of active growth, Angiopoi-
etins (Ang-1 and 2) are expressed, FGFs are produced by
RPE and EC, and TGF-
β
is produced by the RPE
(43-45)
.
CNV stabilizes during the active stage due to a steady
state established between MMP and tissue inhibitors
of metalloproteinases, Ang-1 and 2, PEDF and VEGF,
PDGF and VEGF, plasminogen and fibrin, and oth-
ers
(36,46)
. At some point the balance shifts toward anti-
angiogenic, antiproteolytic and antimigratory activity
resulting in the involutional stage of CNV. When this
occurs the angiogenic/proteolitic/migratory cytokine
production decreases with a shift toward TGF-
β
and tis-
sue inhibitors of metalloproteinases production by the
RPE
(36)
. In this involution stage the CNV may become
collagenized and form a disciforme scar.
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