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Molecular underpinnings of corneal angiogenesis: advances
over the past decade
Nizar Saleh Abdelfattah1, Mohamed Amgad2,
Amira A. Zayed3, Heba Hussein4, Nawal
Abd El-Baky5
1Doheny
Image Reading Center, Doheny Eye Institute, Los Angeles, CA 90033, USA
2Faculty
of Medicine, Cairo University, Cairo 11111, Egypt
3Department
of Oncology, Mayo Clinic, Rochester, Minnesota 55904, USA
4Faculty of Oral
and Dental Medicine, Cairo University, Cairo 11111, Egypt
5Antibody
Laboratory, Protein Research Department, Genetic Engineering and Biotechnology
Research Institute, City for Scientific Research and Technology Applications,
Alexandria 22033, Egypt
Correspondence to: Nizar
Saleh Abdelfattah. Doheny Image Reading Center, Doheny Eye Institute, 1355 San
Pablo Street, Suite 100, Los Angeles, CA 90033, USA. nizar@ucla.edu
Received: 2015-04-30
Accepted: 2016-01-19
Abstract
The cornea is maintained in an avascular
state by maintaining an environment whereby anti-angiogenic factors take the
upper hand over factors promoting angiogenesis. Many of the common pathologies
affecting the cornea involve the disruption of such equilibrium and the shift
towards new vessel formation, leading to corneal opacity and eventually-vision loss. Therefore
it is of paramount importance that the molecular underpinnings of corneal
neovascularization (CNV) be clearly understood, in order to develop better
targeted treatments. This article is a review of the literature on the recent
discoveries regarding pro-angiogenic factors of the cornea (such as vascular
endothelial growth factors, fibroblast growth factor and matrix
metalloproteinases) and anti-angiogenic factors of the cornea (such as
endostatins and neostatins). Further, we review the molecular underpinnings of
lymphangiogenesis, a process now known to be almost separate from (yet related
to) hemangiogenesis.
KEYWORDS: cornea; neovascularization; angiogenesis; lymphangiogenesis;
vascular endothelial growth factor
DOI:10.18240/ijo.2016.05.24
Citation: Abdelfattah NS, Amgad M, Zayed AA,
Hussein H, Abd El-Baky N. Molecular underpinnings of
corneal angiogenesis: advances over the past decade. Int J Ophthalmol 2016;9(5):768-779
Corneal avascularity comprises its main functionality
index as a lens. This article reviews the literature on corneal
neovascularization (CNV) promoted by proteins such as vascular endothelial
growth factors, fibroblast growth factor, and matrix metalloproteinases, and
subsequently inhibited by endostatins, angiostatins, and related
anti-angiogenic factors. It also reviews the normal versus pathogenic changes
in corneal immunity leading to new vascular formation.
CNV is induced by various stimuli mainly associated
with inflammation, trauma, transplantation, and infection of the ocular surface[1-2]. Both
corneal hemangiogenesis and lymphangiogenesis are promoted or inhibited by a
balance of mediators, including the dynamics between pro-angiogenic and
anti-angiogenic substances. In corneas diseased by inflammation, infection,
degeneration, transplantation, or trauma, the normal balance is shifted towards
the pro-angiogenic status, leading to corneal hemangiogenesis and/or lymphangiogenesis.
Major Angiogenic Proteins of the Cornea
Vascular
Endothelial Growth Factor (VEGF) VEGF-A is known to be linked to blood vessel
formation in a wide range of events; including embryonic and physiologic
growth, vascular pathologies and malignant tumor neovascularization. It acts
directly on blood vessels by stimulating endothelial cell mitosis, migration,
dissolution of original vessel membrane, and formation of new capillary tubes [3].
Following
the discovery of VEGF, a series of subtypes were identified and named in
alphabetical order: VEGF-A, VEGF-B, VEGF-C, and VEGF-D. Nevertheless, the chief
VEGF was and still is VEGF-A. A wide range of heterogeneous cells were proven
to secrete VEGF-A, including macrophages, pericytes, T-cells, astrocytes,
fibroblasts, and retinal pigment epithelial cells [3].
VEGF
has multiple isoforms, with its encoding gene comprised of eight exons. With
differential pre-mRNA splicing, a single VEGF gene gives these different
isoforms. Examples of these isoforms include VEGF121, VEGF165 and VEGF189.
These numbers refer to number of amino acids composing the protein. These
isoforms have different properties based on the presence of absence of the
C-terminal protein domains encoded by exons 6 and 7. Also, these isoforms
constitute a reservoir of growth factors acting without gene transcription.
Moreover, interaction of VEGF165 isoform with heparan sulfate proteoglycan-Glypican-1 had been
reported to play a role in extending the half-lives of the isoform in the
process of hypoxia induced angiogenesis [4].
Alternative
splicing of VEGF gene yields five isoforms of VEGF-A, including (VEGF115, VEGF
121, VEGF 165, VEGF 189, and VEGF 206) [5]. The shorter isoforms have more distinctive
functions like the mitogenic activity of VEGF121 and VEGF165, and the more
powerful angiogenic activity of VEGF121 than other longer isoforms [6].
VEGF proved its importance based on the inhibition of neovascularization
in rat model following stromal implantation of an anti-VEGF-A blocking antibody [7].
VEGF
binds to different surface receptor proteins (VEGFR). VEGFR-1 is a
transmembrane receptor tyrosine kinase while VEGFR-2 is a major signaling
receptor for VEGF. Additionally, heparan sulfate proteoglycan (HSPG) is
low-affinity class of VEGF receptors that modulate the activities of wide range
of heparin-binding growth factors, morphogens and chemokines [4].
Basic
Fibroblast Growth Factor Among
the 23 heparin binding peptides fibroblast
growth factor (FGF) family, basic fibroblast growth factor (bFGF)
is a member that is hugely expressed in developing and adult tissues during
cellular differentiation, angiogenesis, mitogenesis and wound repair. Moreover,
it is upregulated after tissue injury and in stromal fibroblast/vascular
endothelial cell co-cultures. FGFs mediate their action through interaction
with peptide receptors (fibroblast
growth factor receptors, FGFR), namely FGFR-1,
-2, -3, and -4. Potential FGF- mediated intracellular signaling events are possibly
present, also different FGFR isoforms show unique biological functions [8].
Besides,
the diversity of FGFR biological response is manifested by its tissue-specific
expression, which is regulated by differences in ligand function and
specificity. The growth factor receptors being regulated are of great
significance in the management of complex physiological processes [9-11].
FGFs
share in a diverse set of actions modulated FGF-Receptor isoforms. FGF-1 is
found in normal corneal epithelium, and differs from FGF-2 in that it is
upregulated in injured cornea and in co-cultures of keratocytes and vascular
endothelia. On the one hand, bFGF binds to Bowman’s membrane and Descement’s
membrane in healthy corneas, yet on the other hand, it binds to vascular
basement membranes of neovascularized corneas [12].
In
fact, it is believed that bone marrow acts as a store of bFGF and VEGF,
sequestering them in order to balance anti-angiogenesis [13].
Besides, the maturation of new blood vessels and the level of FGF binding are
related.
Newly
formed corneal vessels show similar binding capacities in comparison to normal
limbal vessels. This has been linked to heparin sulfate proteoglycans and thus
stresses on the role of extracellular matrix (ECM) components in the regulation
of corneal angiogenesis [14].
The
levels of FGF-1, 2, 3, 7, and 22 are found to be increased in alkali wounding
model at 7 and 14d post-wounding [2]. It is thought that bFGF function in
corneal angiogenesis is mediated through its effect on VEGF-A, -C and -D
production. bFGF promotes angiogenesis greatly through this action.
Angiogenic
Interaction Between Vascular Endothelial Growth Factor and Basic Fibroblast
Growth Factor From the increased
researches in the past decade on characterization of interaction between
multiple membrane-bound receptors, a new hypothesis emerged. It stated that,
membrane-anchored receptors associate and coordinate with each other to
cooperatively induce an array of intracellular signaling cascades, instead of
transmitting signals across the membrane individually. Instead of working
individually it was observed that there is an interplay between FGF and VEGF
signaling for the maintenance of endothelial junctions and vascular integrity
during angiogenesis [15-16].
Also,
a recent study about mustard intoxicated subjects who developed CNV found a
significantly increased levels of growth factors, specifically VEGF-A165, bFGF
and platelet derived growth factor-BB (PDGF-BB) [17].
FGF-VEGF
signaling balance is assumed to lie at the center of the regulation of
permeability and angiogenesis. They are both important angiogenic growth
factors. As soon as VEGF activates VEGFR-2 (a.k.a. FLK-1/KDR), the receptor undergoes auto-phosphorylation on
specific tyrosine residues, followed by the addition of Tyr(P) residues on signaling proteins and adapter that contain
the Src homology domain 2 (SH2)[18].
As
a result the receptor complexes and adapter activate multiple intracellular
pathways through some effectors like focal
adhesion kinase (FAK) and mitogen-activated
protein kinases (MAPK) [19-20].
Flk-1/KDR
can also trigger other cascades including PI3K-dependent AKT/PKB and
phospholipase C-g (PLC-g)[21-22].
Flk-1/KDR-mediated intracellular signaling seems to be similar to bFGF
signaling pathway; however, various lines of evidence suggest that bFGF-induced
angiogenesis is independent of Src
kinase activity unlike VEGF signaling [23].
In
spite of the extensive research on bFGF- and VEGF induced angiogenesis, the
complete intracellular signaling pathways that respond to each of them to
induce angiogenesis are not fully understood. Specifically, how these pathways
interact with molecular regulators is not well documented. It is suggested
recently that membrane-type 1
metalloproteinase (MT1-MMP) may be one of many
factors involved in connecting the two pathways of VEGF and FGF signaling [2]. It
has been showed that MT1-MMP increased bFGF- induced VEGF upregulation and CNV
in mice synergistically [24].
Besides,
MT1-MMP raises bFGF-induced VEGF upregulation in enzymatically inactive MT1-MMP
corneal stromal fibroblasts; which suggest that linking the VEGF and FGF
signaling pathways may be in part due to MT1-MMP enzymatic activity.
Minor
Angiogenic Proteins of the Cornea
Decorins Decorins are members of
the small leucine-rich proteoglycan (SLRP) family, which in turns belongs to a
family of differently functioning molecules that are involved in the regulation
of collagen fibrillogenesis, direct modulation of cell behavior and binding and
inactivation of cytokines. Decorins consists of a protein core containing
leucine repeats with a glycoseaminoglycan (GAG) chain of either dermatan
sulfate or chondoroitin sulfate [25-27].
It
has been demonstrated that decorins may regulate corneal angiogenesis [2,28].
Their effects on corneal angiogenesis in mice have been heavily studied, as
well as the effects of biglycan and fibromodulin [29]. Using chemical cauterization, it was verified that
in decorin-deficient mice (unlike biglycan and fibromodulin-deficient corneas),
the growth of corneal vessels is significantly diminished compared to wild type (WT).
Recently,
it was observed that bFGF induce MT1-MMP expression but diminish decorins
expression [30].
Furthermore, it was demonstrated that MT1-MMP cleaves decorins in vitro, and that cell lysates from
MT1-MMP-deficient keratocytes do not show decorins processing activity.
Ephrins
and Eph Receptors One of the largest known
families of receptor tyrosine kinase (RTK) is the Eph/ephrin complex. It
consists of 14 receptors and 8 ligands, and its family members are
subcategorized to class A and class B depending on their structure and ligand
binding receptor characteristics [31-32].
In
several vascular endothelial cells, EphB1-B4 and ephrinB1 and B2 were found to
be expressed [33-34].
In adult mice it was demonstrated that EphB1 and ephrinB2 induce corneal
angiogenesis [35],
and that ephrinB1 induces vascular endothelial cell migration, assembly, and
adhesion [36].
Recently,
immunohistochemical studies were used to demonstrate that ephrinB1 and EphB1
are expressed in bbFGF-induced vascular corneas [2], which proves that Eph and
ephrin receptors play a role in corneal angiogenesis [37].
EphrinB1
is expressed in corneal-resident keratocytes and neutrophils. In order to test
Eph and ephrin receptors’ role in angiogenesis, recombinant ephrinB1-Fc (which
induces EphB receptor activation) was used. It was found to promote
bFGF-induced tube formation in an in
vitro aortic ring assay; as well as corneal angiogenesis in-vivo in a corneal pocket assay. These
results suggest that ephrinB1 plays a synergistic role in CNV [2]. Ellenberg et al[2]
also compared ephrinA/EphA expression to ephrinB/EphB expression in
vascularized corneas. bFGF pellets were implanted to induce CNV. The eyes of WT, ephrinB2 tlacZ/+,
and EphB4 tlacZ/+ heterozygous mice were harvested and sectioned 7d
after pellet implantation. Confocal immunohistochemistry was performed to
compare the expression of the Eph/ephrinA family and Eph/ephrinB family. EphA1,
EphA3, ephrinA1, ephrinA2, EphB1, EphB4, ephrinB1, and ephrinB2 were detected
in WT mouse corneal epithelial cells and keratocytes.
Using
immunohistochemistry it was found that EphA2 was only located in the epithelial
cells, while EphA3, ephrinA1, EphB1, EphB4, and ephrinB1 were localized in
corneal epithelium and stroma. However, in neovascularized corneas; ephrinB1
was mainly localized to keratocytes around the vessels, and ephrinB2, EphB1,
and EphB4 were mainly located simultaneously with CD31 in the vascular
endothelial cells. These studies strengthen the suggestion that Eph/ephrin
family of receptor tyrosine kinases and their ligands may play a role in the
regulation of corneal angiogenesis [2].
Activin
Receptor-like Kinase Activin receptor-like
kinase-1 (ALK-1) is one of the seven type I receptors recognizing transforming
growth factor beta (TGF-β) family proteins [38].
It has been suggested that ALK-1 plays a role in the maturation phase of
angiogenesis [39].
The transfection of a constitutively active form of ALK-1 inhibit not only,
endothelial cell proliferation at the G1 phase of the cell cycle, but also
endothelial cell migration through a modification of the dynamics of
endothelial cell cytoskeleton [40].
Supporting
these results is a zebrafish ALK-1 mutant, vgb, whose vessel dilation
phenotype is reminiscent of ALK-1-/- mice. Its affected vessels
showed an increased number of endothelial cells, supporting a role for ALK-1 in
the inhibition of endothelial cell proliferation.
It
have been demonstrated using the pellet induced CNV model that over
expression of ALK-1 (using naked DNA injection) in mouse cornea does not induce
CNV [2].
Besides, it can prevent growth of new bFGF-induced stromal vessels. All of that
strengthen the possibility that ALK-1 plays an important role in angiogenesis.
Recently,
Ellenberg et al [2] have
described a proteomic approach to investigate the differential protein
expression patterns and identify the physiologically relevant angiogenic and
anti-angiogenic factors involved in the hyaloid vascular system regression.
Differentially expressed proteins were identified using two-dimensional gel
electrophoresis from the lens and vitreous of P1 and P16 mice followed by
nanoflow chromatography coupled with tandem mass spectrometry [41].
Using this approach, the following factors expressed at P16 may be involved in
angiogenesis: tumor necrosis factor-α (TNF-α), hepatoma-derived growth factor
(HDGF), FGF-22,
and kininogen.
Integrins A major family of type I transmembrane
cell surface receptors are the integrins. Currently, 18 individual α subunits
and 8 β subunits have been identified. Integrins are heterodimers composed of
one α and one β subunit [42-43].
It
has been noticed that a significant upregulation of αvβ3 and α5β1 takes place
on activated vascular endothelium during angiogenesis. It is suggested that α5
integrins play a key role during the development of the vascular system [44-45].
Testing that hypothesis with genetic ablation of integrin α5 leads to severe
vascular abnormalities. α5β1 integrin as well as its extracellular ligand
fibronectin which is able to provide proliferative signals to vascular cells
both are upregulated in tumor new blood vessels and plays a role in tumor
angiogenesis and growth. Besides, angiogenesis have been inhibited in-vivo and in-vitro using integrin αvβ3 and αvβ5 antagonists.
On
the other hand, treating animals systemically with an α5β1-inhibiting small
molecule showed significant inhibition of CNV. Combining them to integrin αv
and α5 does not promote the anti-lymphangiogenic effect in vivo [46-47].
Matrix
Metalloproteinases Corneal
extracellular matrix (ECM)
remodeling by matrix metalloproteinases (MMPs) has also been
implicated in corneal angiogenesis and in the maintenance of corneal
avascularity. MMPs are described as a group of proteolytic enzymes that are
zinc-binders, and participants in ECM remodeling, neovascularization, and
lymphangiogenesis.
MMPs
is a large family that involve 25 enzymes described so far, not less than 15 of
which have been identified in the cornea; (MMP-1, -8 and -13) represent the
collagenases, MMP-2 and -9
represent the gelatinases A and B, MMP-3, -10 and -11 represent
the stromelysins, MMP-7 is the matrilysin and MMP-12 is the macrophage
metalloelastase while MMP-14, -15, -17, -24 and -25 all represent the membrane
type of MMPs[48-52].
After
several studies it became clear that MMP-mediated proteolysis induce several
important biological functions including: 1) changing structural matrix proteins into
signaling molecules (e.g. collagen
XVIII that is present in the cornea and having an NC1 domain which is
anti-angiogenic); 2)
changing the structure of matrix
proteins like cleaving perlecan and decorin-corneal ECM proteoglycans; 3) changing the architecture of the tissue
(e.g. cleaving E-cadherin); 4) changes in chemotaxis; 5) inducing proliferation like its
action through epidermal growth factor receptor ligand processing; 6) ensuring the cell survival (e.g. neuronal survival factor); 7) activating some latent signaling molecules
(e.g. TNF-a shedding and IGF binding
protein cleavage); 8)
changing the range of signaling
molecule action (e.g. changing
the range of VEGF diffusion); 9) causing
tissue differentiation (e.g.
adipose tissue maturation)[52-55].
Increased
expression of MMPs in corneas during angiogenesis has already been demonstrated
[56-57].
However it is still vague what is their definitive role in regulation of
angiogenesis because they can act as pro- and anti- angiogenic factors at the
same time, which might be explained by their ability to degrade the ECM, allowing tissue
invasion by endothelial cells bearing MMP, and to generate anti-angiogenic
fragments from their precursors [52,58-59].
In
the following sections, additional information on the roles of MMP-2, MMP-7,
and MT1-MMP in corneal angiogenesis are highlighted.
Matrix
Metalloproteinase-2-Gelatinase
A Gelatinase-A
(MMP-2) has always been linked to angiogenesis. It was demonstrated that it is
pro-angiogenic through facilitating vascular invasion by direct matrix
degradation or through releasing matrix bound cytokines or growth factors [52,60-61].
MMP-2
expression by epithelial cells and stromal keratocytes has been confirmed by in
situ hybridization [49].
Besides, its physiologic role in angiogenesis has been defined: when MMP-2
deficient mice were used to determine the role of MMP-2 in vascular endothelial
cell migration and tube formation in
vitro using aortic rings, it was demonstrated that bFGF mediated angiogenic
response was diminished in mice lacking the functional MMP-2 gene compared to WT animals [50].
On
the other hand, endothelial cells from MMP-2 lacking mice failed to display
normal outgrowth after adding 5 ng/mL bFGF, which lead to the suggestion that
the difference in bFGF-induced angiogenesis between MMP-2 lacking mice and WT
mice may be due to the difference of vascular endothelial cells; as it could be
inconvenient for endothelial cells lacking functional MMP-2 to traverse the
basement membrane [2].
The
MMP-2-null mice developed almost normally, and bFGF induced corneal
angiogenesis even in the MMP-2-mutant mice, clearly indicating that the
angiogenic process is not totally dependent on MMP-2. In another experiment,
MT1-MMP null mice showed complete absence of corneal angiogenesis which lead to
the suggestion that MT1-MMP by itself has an essential role in the process of
angiogenesis [51].
Based on these data, further research is needed to explain the discrepancy
between MMP-2 and MT1-MMP effect on angiogenesis.
Studies
show that through intramolecular processing, MMPs can modulate the
bioavailability of VEGF; a group of MMPs can cleave the matrix-bound isoforms
of VEGF releasing soluble fragments to promote capillary dilatation of existent
vessels [59,62-63].
In
recent researches, MMP-2 could cleave connective tissue growth factor (CTGF)
and heparin affin regulatory peptide (HARP) and inactivate them upon
proteolysis. As these two are angiogenic and mitogenic cytokine inhibitors in
complex with VEGF, cleaving those releases the VEGF. As a result, MMP-2
possesses potential pro-angiogenic activity by releasing intact VEGF from HARP
or CTGF cytokine inhibitory complexes [62].
Matrix
Metalloproteinase-7 (Matrilysin)
Matrilysin also called MMP-7 is
expressed in basal epithelial cells in the migration and proliferation phases
of corneal wound healing after excimer
keratectomy [48-49].
Matrilysin has catalytic action against a wide range of ECM substrates e.g. gelatins (I, III, IV, and V),
fibronectin, elastin, collagen IV, laminin and entactin-nidogen [64]. At the same time,
it can cleave factors which modulate angiogenesis like CTGF, sVEGFR-1,
plasminogen and collagen XVIII. It has been positively stained in basal
epithelium of pterygium specimen suggesting its involvement in pathogenesis and
angiogenesis in pterygium [65].
The
anti-angiogenic role for MMP-7 in cornea is based on the fact that MMP-7
cleavage of corneal collagen XVIII yields a 28-kDa fragment which contains the
endostatin domain of collagen XVIII that shows potent anti-angiogenic function [58]. Also in MMP-7
knock-out (KO) mice,
in the keratectomy wounding model, a decrease in the levels of anti-angiogenic
factors tilts the balance towards corneal angiogenesis [2].
Recent
researches show that the induction of new vessel formation in diseased corneas
involves not only upregulation and activation of angiogenic factors such as
VEGF and bFGF but also suppression of anti-angiogenic factors.
Based
on the observation that MMP-7 cleaves plasminogen and collagen XVIII in vitro to generate anti- angiogenic
factors e.g. angiostatin and endostatin respectively
suggest that the reduction of MMP-7 derived endostatin and/or angiostatin in
the cornea may contribute to CNV after excimer
keratectomy in MMP-7 KO animals [2].
Membrane-type
1 Metalloproteinase MT1-MMP is the most
important MMP in angiogenesis. MT1-MMP expression in the cornea has been
detected in the epithelium and stromal keratocytes during wound healing [49]. Its importance
becomes evident in that it is the only MMP that its absence is lethal
demonstrated by genetic KO of MT1-MMP in mice lead to death within three to
four weeks, unlike other MMPs who’s genetic KO might affect angiogenesis but is
never lethal to the animal.
MT1-MMP
proved to be important for angiogenesis and its absence causes delayed vascular
development and impaired CNV by bFGF [51].
Further studies have been carried out to understand its role using genetic KO mice, antibodies
against MT1-MMP, animal models and other methods[2]. It was noticed that there is an enhanced MT1-MMP
expression in alkali wounded CNV. In addition using reverse
transcription-polymerase chain reaction (RT-PCR) to evaluate the
expression of growth factor receptors in WT, MT1-MMP KO, and MT1-MMP (knochin) KI mouse cornea
stromal fibroblasts, it was found that no significant difference existed in the
expression patterns of PDGFa, PDGFb, and VEGFR-1 in either type of cells.
On
the other hand, endothelial growth factor receptor (EGFR) expression was
decreased in MT1-MMP KO cells when compared to the WT and
MT1-MMP KI cells, suggesting that MT1-MMP play a role in EGFR expression
regulation. Since EGFR is also fibroblast proliferation and migration
regulator, it may be responsible for some of MT1-MMP pro-angiogenic effects [66].
Angiogenic
Interaction Between Membrane-type
1 Metalloproteinase and Vascular Endothelial
Growth Factor/ Fibroblast Growth Factor There
have been new studies that elaborated the signal pathways involved in the
interaction between these molecules and their role in CNV[67]. It was suggested that MT1-MMP may link the two
signaling pathways of VEGF and FGF[24],
but its specific role in linking them remains vague. The pro-angiogenic role of
MT1-MMP has been reported to be in part mediated through the upregulation of
both VEGF transcription and translation[68].
Immuno-histochemistry
and RT-PCR analysis of human glioma tissue samples proved a functional link in
tumor angiogenesis between MT1-MMP and VEGF by giving evidence to the link
between their expressions[69].
Further
evidence is the correlation between VEGF stimulation and hypoxia-induced
upregulation of MT1-MMP in the murine bone marrow -derived stromal cells.
Putting all these data together gives a strong evidence of linkage between
signaling pathways of MT1-MMP and VEGF, which may play a role in regulating
corneal angiogenesis[59].
The FGF and MT1-MMP interaction has been well documented: FGF-1 induction of
MT1-MMP transcription in LNCaP prostate carcinoma cells has been reported.
Besides, FGFR-1 and STAT3 involvement in FGF-1 mediated MT1-MMP expression has
also been reported[70].
bFGF induced CNV increased when bFGF pellets have been used in combination with
naked MT1-MMP DNA plasmid injection[2].
The interplay between MT1-MMP, VEGF, and bFGF has been demonstrated by
experiments in which VEGF and MT1-MMP expression increased after implantation
of bFGF- pellets in murine cornea.
Corneal
angiogenesis privilege (CAP) is shown to be secondary to the
interaction of multiple anti-angiogenic factors. Most notable of which are
angiostatin, angiostatin-like fragments[71],
and endostatin[72].
Other potent anti-angiogenic factors that modulate CAP include restin,
arresten, canstatin, tumstatin, and pigment epithelial-derived factor (PEDF)[73].
They
can be generally classified into, endostatin/endostatin analogues, and plasminogen/serine
protease inhibitors.
Endostatin/Endostatin
Analogues
Endostatin Endostatin
has been shown to inhibit in-vitro
VEGF mediated endothelial migration and proliferation[74],
as well as decrease tumor progression in in-vivo
murine models. Moreover, endostatin has been successfully administered in
corneal assays, with significant reduction in bFGF mediated angiogenesis[75].
The
mechanism of action of Endostatin is relatively complex. It exerts its actions
through primarily associating with tropomyosins, integrins, VEGF receptors,
MMPs, and glypicans. Its action on VEGF is in the form of; Blockage of VEGF
cell surface receptor KDR/FLK1, downstream inactivation of ERK, MAPK, and
P125FAK, Ultimately, arrest of cell cycles in G1, with inhibition of mitogenic
responses in vascular endothelial cells[76].
In
addition to VEGF antagonism, endostatin enhances vascular endothelial apoptosis
via increasing the activity caspase 3
[77].
Alongside
angiogenesis inhibition, endostatin has been shown to affect lymphogenesis as
well. Recombinant endostatin was shown to inhibit the proliferation and
migration of lymphatic endothelial cells, in
vitro[78].
One possible mechanism for this activity is the ability of endostatin to
inhibit distribution of VEGF-C-producing tumor-associated inflammatory cells
and to induce the apoptosis of VEGFR-3 expressing cells [79].
Neostatin There
are two major types of neostatins, both of which have been proven as potent
angiogenesis inhibitors. Neostatin-7 (formed via MMP-7's cleavage of collagen XVIII), and neostatin-14 (formed via MT1-MMP-mediated cleavage of
collagen XVIII) [79].
Both
MMP-7 and MT1-MMP are expressed by corneal epithelial cells [48], where collagen
XVIII is actively secreted as well[59].
Moreover, it was demonstrated that recombinant neostatin-7 blocks bFGF-induced
corneal angiogenesis and lymphangiogenesis [80].
This strongly shows the important role of corneal epithelium in maintaining CAP.
Other
Miscellaneous Molecules Arresten,
canstatin, and tumstatin are three type IV collagen-derived proteins that were
shown to have potent anti-angiogenic activity[81-84].
Arresten
actions are mediated via α1β1
integrin receptors. It successfully inhibits bFGF-induced proliferation,
migration, and tube formation of cultured endothelial cells[82,85-86].
Another
molecule, canstatin, acting via α3β1,
αɣβ3, and αɣβ5 integrin receptors, has diverse
functions. It causes suppression of tumor growth, inhibition of endothelial
cell proliferation and migration, and induction of endothelial cell apoptosis [87-89].
Also,
tumstatin which is a 28 kDa protein derived from type IV collagen α3 chain,
exerts its action via αɣβ3 and α6β1
integrins receptors. It shares in suppression of tumor growth, inhibition of
endothelial cell proliferation and migration, induction of endothelial cell
apoptosis, and inhibition of protein synthesis [84,90-91].
Tumstatin
can inhibit protein synthesis through the inhibition of phosphorylation of FAK,
induced in endothelial cells via attachment
to vitronectin, and by inhibiting the activation of PI3-kinase through αɣβ3
binding [84,92].
Plasminogen-derived
and Serine Protease Inhibitors of Angiogenesis
Angiostatin Angiostatin
is a complex molecule that can inhibit primary and secondary tumor growth. One
of the enzymes responsible for the generation of angiostatin in Lewis lung
carcinoma has been identified as a macrophage derived metalloelastase (MMP-12)[93].
However, human matrilysin (MMP-7) and neutrophil gelatinase B (MMP-9) can also
convert plasminogen to angiostatin fragments [94].
The
suppressive action of recombinant angiostatin on in-vivo tumor growth and metastasis in animal models has also been
demonstrated[95].
Moreover, angiostatin was proven to be a non-toxic inhibitor of neovascularization
when injected to tumor-bearing mice[96].
One
mechanism that explains these actions is down-regulation of endothelial cells
migration and proliferation, through binding to ATP synthase and decreasing endothelial
cell ATP production[97].
Another way is induction of endothelial cell apoptosis and arrest at the G2 to
M transition phase [98].
Another
possible mechanism for angiostatin is its binding to integrin αvβ3; thereby
inhibiting its actions. Typically plasmin binds to αvβ3 through its kringle
domains, promoting endothelial cell migration. This process can be disrupted
through anti-integrin αvβ3 agents (i.e.
angiostatin) and a serine protease inhibitor [99].
Angiostatin
and angiostatin-like molecules play an important role in maintaining corneal
avascualrity after injury, and it was shown that their expression in corneal
epithelium increases remarkably at these events[100].
Moreover, corneal segmental neovascularization was demonstrated after excimer laser
keratectomy followed by treatment with anti-angiostatin (anti-LBS or anti-
K1e3) antibody injection, further affirming the role of angiostatin [2].
Pigment
Epithelium Derived Factor A
member of the serine protease family, PEDF is a potent anti-angiogenic factor,
expressed within endothelial and corneal epithelial cells[101].
It typically works through binding to surface receptors, such as
glycosaminoglycans and collagen I[102].
Furthermore,
the recombinant PEDF inhibited CNV as well[103].
These findings point towards an essential function of PEDF in maintaining
avascular environment of the cornea. Other works established similar roles for
PEDF in the vitreous, aqueous humor, and retina[2].
Given
its effectiveness against multiple inducers of angiogenesis, as VEGF and
interleukin-8 (IL-8), and its multiple sites of action, PEDF derivatives can
prove highly effective in reversing pathological ocular angiogenesis processes.
Molecular underpinnings of lymphangiogenesis
The
process of lymphangiogenesis was thought to have the same molecular
underpinnings as hemangiogenesis for a long time. It is only relatively
recently that lymphangiogenesis started to have a separate entity, especially
after the discovery of the key lyphatic endothelial cells (LEC) marker,
lymphatic vessel endothelial hyaluronan receptor (LYVE-1) [101]. The formation of lymphatics can be summarized in the following steps [104]:
1) Endothelial cells
differentiate from angioblasts into venous endothelial cells and arterial
endothelial cells.
2) Venous endothelial
cells highly express VEGFR-3 and a subset of them begins to express LYVE-1 as well. This subset
represents the precursors of LEC's [105].
Bone marrow-derived cells, including macrophages, may also transdifferentiate
into endothelial cells [106].
3) LEC precursors begin to
express the transcription factor SOX18, which is present upstream of another
transcription factor, Prox-1 [107].
SOX 18 induces the expression of Prox-a
and triggers a set of incompletely-understood events that eventually determine
the differentiated fate of LEC's [108].
In fact, Prox-1 is known to be expressed in a polarized manner in
differentiating LEC's and is believed to be a "master switch" in LEC
differentiation.
4) LEC precursors express
Neuropilin-2 (NP-2)[109].
NP-2, while not triggering downstream signaling itself, sensitizes the LEC to
VEGF-C stimulation and acts synergistically with VEGFR-3[109].
5) At this stage, the
proliferating lymphatics begin to form lateral extensions from the veinules,
known as "lymphatic sacs" [107].
6) LEC's start expressing
the transmembrane protein, podoplanin[110-111].
In turn, podoplanin binds to CLEC-2 receptors on platelets and activates SLP76
and Syk, leading to platelet aggregation [112].
7) The aggregated
platelets block the connection between the developing lymphatic and the veinule
from which it budded, eventually leading to physical separation of the two
entities.
8) FoxC2 and NFACT-1
(nuclear factor of activated T cells), both of which are transcription factors
downstream of VEGFR-3, cooperate in controlling genes that are important in
further differentiation of the lymphatic tree, including lymphatic valves [113].
TGF-b and TNF-a both act
to inhibit lymphangiogenesis [114-115]. On the other hand, VEGF-A, VEGF-C, FGF-2, IGF-1, IL-1B, HGF and PDGF have
all been shown to simulate both hemangiogenesis and lymphangiogenesis (as has
been discussed in detail earlier). It is noteworthy that the growth factors and
cytokines that stimulate hemangiogenesis and lymphangiogenesis greatly overlap.
Nonetheless, VEGF-C/VEGFR-3 signalling seems to be more specific to
lymphangiogenesis and VEGF-3 ceases being expressed in adult blood vessels,
with the exception of fenestrated vessels of endocrine glands [116-117]. Another factor that differentiates lymphangiogenesis from hemangiogenesis
is the role of a5b1 integrins in lymphangiogenesis. An a5b1 antagonist results in a hemangiogenesis-dominant response to CNV
induction [118]. Table 1 highlights some of the differences between hemangiogenesis and
lymphangiogenesis [106,116-134].
Table 1
Differences between hemangiogenesis and
lymphangiogenesis
|
Parameters |
Hemangiogenesis |
Lymphangiogenesis |
|
Corneal privilege mechanism |
Upregulation of anti-angiogenic factors and
downregulation of angiogenic factors Soluble VEGFR-1 and ectopic VEGFR-3 act as
"VEGF traps" to prevent hemangiogenesis[117] |
Soluble VEGFR-2 and VEGFR-3 act as "VEGF trap" and selectively suppresses
physiologic growth of lymphatics[117,121] |
|
Formation |
Sprouting or budding from post-capillary veinules |
LEC's arise from either: Bone marrow-derived cells, such as
transdifferentiated macrophages[106] Primitive veinules and local lymphangioblasts
(described in detail in the text) |
|
Role of macrophages |
Providing a temporary scaffold for the new vessels[122] Provide paracrine support for vascular networks[123] Interact physically with the blood vessels[124] |
Transdifferentiate into endothelial cells, thus
participate -structurally- in lymphatic vessels[122] Secrete paracrine factors, most importantly VEGF-A[128] Act as "guide cells" that guide tip cells
into finding and anastomosing with tip cells from other sprouting lymphatics[125] |
|
Expression of VEGFR-3 |
Expressed during early stages of endothelial development. Fully
developed blood vessels seldom contain VEGFR-3, with the exception of fenestrated
blood vessel of endocrine glands[116] |
Highly expressed by LEC's |
|
Role of VEGF-C and VEGF-D |
Hemangiogenic properties through binding to VEGFR-2[126] |
Both copies of the VEGF-C gene are needed
(haploinsufficiency)[130] Bind to VEGFR-3 and promote venous endothelial
differentiation into lymphangioblasts[110,130] VEGFR-3 blockade results in a
hemangiogenesis-dominant cornea[131] VEGF-C plays a key role in development of the
lymphatic vascular tree, but is not needed to maintain lymphatics after that
have already been developed[132] Deletion of VEGF-D, in contrast, does not affect
lymphatic vascular development[130] |
|
Role VEGF-A[124-125] |
Binds to VEGFR-1 and -2 to promote hemangiogenesis |
Binds to VEGFR-1 and -2 to promote
lymphangiogenesis Also acts indirectly through recruitment of
macrophages |
|
Response to VEGF-A[118]. |
Early appearance of vessels in response to low VEGF-A levels |
Delayed appearance of vessels and higher VEGF-A concentrations required1 |
|
Role of FGF-2 |
Stimulates angiogenesis only at high doses (80-100 ng)[133] |
Low dose (12.5 ng) selectively stimulates lymphangiogenesis[134] |
|
Regression after pathologic invasion of cornea[131] |
Late |
Early |
|
Corneal transplant rejection[115] |
Less important role |
Important role |
1The
delayed appearance of lymphatics is attributed to the fact that sprouting blood
vessels upregulate VEGFR-2, which traps VEGF-C and prevents it from forming new
lymphatics at the early phases. This is hypothesized to allow more time for the
immune cells to reach the inflammatory site before being cleared by lymphatics.
The cornea is maintained in an avascular state through
a balance between naturally present pro-angiogenic and anti-angiogenic chemical
mediators. CNV continues to be an incompletely understood process that requires
further research and funding to reveal its molecular pathways.
While hemangiogenesis and lymphangiogenesis were
seldom distinguished in the past decades, recent attention has been geared
towards understanding the differences between these two different, yet
interdependent processes.
We think that more attention is needed in the upcoming decade to address
and enhance our understanding of the molecular and genetic processes hidden
under the mere manifest blood vessel.
ACKNOWLEDGEMENTS
Conflicts of interest: Abdelfattah NS, None; Amgad M, None; Zayed
AA,
None; Hussein H, None; Abd El-Baky N, None.
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