|Molecular Vision 2003;
Received 10 June 2003 | Accepted 15 December 2003 | Published 22 December 2003
Choroidal neovascularization: a wound healing perspective
David Kent,1,2 Carl
1Eye Service, Aut Even Hospital, Kilkenny, Ireland; 2Unit of Ophthalmology, Department of Medicine, University of Liverpool, United Kingdom
Correspondence to: David Kent, Eye Service, Aut Even Hospital, Freshford Road, Kilkenny, Ireland; Phone: 353 56 7722346; FAX: 353 56 7762149; email: email@example.com
The process of submacular angiogenesis seen in association with a variety of chorioretinal disorders is termed choroidal neovascularization (CNV). It invariably results in significant and permanent vision loss arising from the development of scar tissue formation. At the cellular level, CNV appears to be a component of several key processes that can be broadly referred to as wound healing or tissue repair. Wound healing involves a coordinated cascade of cellular events driven, in the main, by the production of cytokines and which are interpreted by target cells in the context of a continually evolving extracellular matrix (ECM). A similar process occurs in what is clinically termed CNV. Angiogenesis is just one component of this wound healing process. Other key components include inflammation, matrix deposition and remodelling. Thus, in the context of a tissue repair response, viable treatment options for CNV could include therapies other than those that are currently directed at the angiogenic component of this process.
Choroidal neovascularization (CNV) is a common pathological endpoint in a host of chorioretinal diseases [1-5]. Most often encountered in relation to age-related macular degeneration (AMD), it is a formidable adversary despite a variety of therapeutic approaches. Until we understand more about the primary diseases that lead to CNV and their treatment, present and future therapies will be aimed at modifying the course of CNV development. Currently, virtually all therapies are anti-angiogenic in their application. Yet what we term clinically as CNV is, at the cellular level, much more that an endothelial disease. In addition to the vascular element, this paper will review the non-vascular components to highlight a condition that is essentially a submacular wound healing response. Bearing in mind the concept of tissue repair, this article will conclude by proposing alternative therapeutic strategies other than anti-angiogenic approaches to the treatment of CNV.
Before discussing wound healing in relation to CNV, it is necessary to introduce some general concepts on tissue repair. Wound healing or tissue repair involves a wide range of cellular, molecular, physiological and biochemical events that usually results in rapid re-establishment of anatomical or physiological barriers. Where injury to the skin is concerned we wound term this re-establishment as wound closure. At this stage it is important to differentiate between repair and regeneration. Repair "is an adaptation to loss of normal organ mass and leads to restoration of the interrupted continuity by synthesis of scar tissue without restoration of the normal tissue." Regeneration, on the other hand, "restores the normal structure and function of the organ ." This article will be confined to wound repair concepts only.
Normal wound healing
The standard model for the descriptive processes occurring in wound repair is the skin and involves a complexity of interactions that typically are divided into three classical consecutive and overlapping phases. These are termed inflammation, tissue formation and tissue remodelling phases [7-10]. Normal wound repair requires a continually evolving interaction among cells, cytokines and the extracellular matrix (ECM). Each phase tends to have a specific duration and is characterised by the presence of precise cellular and extracellular markers consistent with that phase. At any particular stage cytokines and growth factors act as signals, suppressors and promoters that are interpreted by cells in the context of the surrounding ECM .
An example of how the surrounding ECM can influence growth factor affects can be illustrated for tumor necrosis factor-alpha (TNF-α) which is known to activate the genes encoding for various inflammatory mediators [9,10]. TNF-α has also been shown to affect matrix remodelling during wound repair with decreased collagen gene expression and activation of MMP-2 . However, TNF-α can only substantially promote activation of MMP-2 in dermal fibroblasts when the cells are embedded within a collagen type-I matrix and neither collagen or TNF-α individually have any affect on fibroblast mediated pro-MMP2 activation . Furthermore even the same substrates can illicit different affects from cells .
Injury can result from a host of agents including surgery, infection, trauma, ischemia as well as being immune related. The injured tissue, including blood vessels, release soluble mediators called cytokines. These polypeptides stimulate "cross-talk" between cells that give rise to major changes in cell behaviour . Pivotal in the progression to the subsequent phases of wound healing is the release of cytokines such as platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α) and TGF-β from the injured cells. Bleeding and platelet aggregation lead to activation of the coagulation cascade resulting in fibrin clot formation. The presence of thrombin induces platelet degranulation leading to further release of PDGF, TGF-α and -β and epidermal growth factor (EGF). The deposition of adhesive elements such as the glycoprotein fibronectin , and the anti-adhesive matricellular proteins tenascin (TN) , osteonectin or Secreted Protein Acidic and Rich in Cysteine (SPARC) [17,18] and thrombospondin (TSP) [19,20] is also initiated. Together with the fibrin clot, these molecules provide a provisional matrix for cell migration from adjacent uninvolved tissue that heralds the inflammatory phase of wound healing. In the skin, the inflammatory reaction does not subside with epithelialization. It persists during tissue remodelling but is characterised by different cellular composition compared to the acute phase [10,21]. Once the acute phase subsides, lymphocytes become the predominant leukocyte subset . These lymphocytes produce growth factors  and therefore probably contribute to tissue remodelling during the later stages of tissue repair. Mast cells are also being increasingly recognised as an important source of growth factors and are detected at higher frequencies in repair compared to non-injured skin [24,25].
Initially at day one however, it is neutrophils that are the predominant cell type and constitute nearly 50% of all cells at the wound site  and are implicated in wound decontamination through phagocytosis . However, it is the macrophage that invades the wound at the same time, that seems to be the most crucial inflammatory cell in wound healing and as well as playing a role in wound debridement and decontamination, it also plays a central role in wound repair [26,28,29]. By day 2, with a decline in neutrophil numbers, macrophages have become the predominant leukoctye subtype [26,30-32]. It is macrophage-derived cytokines, including PDGF, TGF-α and -β, fibroblast growth factor (FGF), EGF, interleukin-1 (IL-1) and TNF-α, that are essential for the initiation and propagation of new tissue synthesis and the transition to the tissue repair phase at the wound site . The temporal and spatial regulation of leukocytes at the site of the wound appears to be self-regulated by a leukocyte subtype specific chemoattractant cytokines referred to as chemokines [33-35]. These modulators, such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) , have unique activating abilities to guide the various leukocytes during the phases of tissue repair. Furthermore, it is now emerging that chemokines may also play a role in angiogenesis  and in fibroblast-mediated tissue remodelling [37-41].
Tissue formation typically occurs between three and twelve days. Initially there is granulation tissue formation (mainly fibronectin and hyaluronan) by macrophages, newly arrived fibroblasts and endothelial cells. These fibroblasts and endothelial cells also proliferate and begin synthesis of ECM that will support future cell growth and function . Once again it is the release of cytokines and growth factors during the inflammatory phase that provide the stimulus for fibroblast migration and proliferation and include PDGF, TGFβ and FGF. Activated fibroblasts themselves then provide an autocrine feedback loop by expressing PDGF and TGF-β, thus further amplifying the wound repair process. As fibroblasts invade the clot, it is lysed to allow the further deposition of early granulation tissue, comprising of collagens, fibronectin, laminin and hyaluronan, and occurs under the influence of several cytokines of which TGF-β is probably the most potent [43-47]. This rapid change from fibrin clot to granulation tissue occurs initially in the periphery of the wound and moves centrally until the entire wound is occupied by granulation tissue. Therefore at any given time, the ECM at the wound edge differs significantly from the centre. These first days of matrix deposition demonstrate an abundance of type III collagen but under the influence of EGF, it eventually takes on the characteristics of unwounded skin with a preponderance of the highly cross-linked collagen type I . Angiogensesis is stimulated by the necessity to meet the high metabolic requirements for the synthesis and maintenance of these newly formed tissues and the hypoxia occurring at the centre of the wound .
Matrix production and remodelling almost start concomitantly with granulation tissue formation and, together with contraction, can begin as early as day 3 . Although new ECM production continues, a dynamic equilibrium exists between synthesis and degradation of extracellular components  such that there is overall a net reduction in matrix components such as collagens, laminin and proteoglycans due to enzymatic destruction of old matrix by a family of enzymes known as matrixmetalloprotineases (MMPs) . The MMPs are a family of endopeptidases that selectively degrade components of the ECM and are produced by a variety of cell types including fibroblast and macrophages . They are secreted as zymogens and must be activated in the ECM compartment. It is the presence of endogenous inhibitors, known as tissue inhibitors of matrixmetalloproteinases (TIMPs), that regulate the overall activity of MMPs. Several of the components of the early wound matrix, including SPARC, TSP and fibronectin, can induce in vitro production of MMPs [52-54]. In addition to the action of the MMPs, fibroblast secretion of matrix is inhibited by TNF-α and FGF-2 and the fibroblasts themselves become refractory to TGF-β [24,55,56]. Simultaneously there is a decrease in capillary density and the appearance of larger mature blood vessels. Finally, there is a decrease in cell number at the wound site through apoptosis and eventually wound quiescence ensues. The clearance of these apoptotic cells appears to be mediated through TSP expression by macrophages . The net result of these processes is wound closure and although the precise mechanism by which cells contract scar tissue is still controversial , several theories have been proposed [58-64].
Angiogenesis in normal wound healing
Angiogenesis, the formation of new blood vessels from the pre-existent microvasculature, is an essential component of normal wound repair. Initiated immediately following injury, it delivers oxygen, nutrients and inflammatory cells to the site of injury. It also assists in the removal of debris and in the development of granulation tissue formation and ultimately wound closure. Both angiogenic agonists and antagonists are identified at various stages of the wound repair process [28,53] suggesting a dynamic balance of stimulators and inhibitors that favour either vascular growth or regression . Because angiogenesis is an invasive process, it also requires proteolysis of the ECM in addition to proliferation and migration of endothelial cells and the synthesis of new matrix components .
Immediately following injury, there is tissue destruction and hypoxia. Potent angiogenesis factors such as FGF-1 and FGF-2 are released secondary to cell damage while tissue hypoxia is a potent stimulator of Vascular endothelial growth factor (VEGF) family members and its receptors, VEGF-R1, R2 and R3 [66-68]. In addition, the arrival of macrophages leads to the release of more angiogenic factors including further VEGF . VEGF is a diffusible mitogen and angiogenic factor that can also increase vascular permeability, hence its original name of vasopermeability factor or VPF . Several cell types secrete VEGF, while its receptors are expressed predominantly but not exclusively on endothelial cells.
It is now thought that FGF-2 (originally called basic FGF) is responsible for early angiogenesis (the first 3 days in skin) and after this with advanced granulation tissue deposition, VEGF becomes crucial . Unlike VEGF, FGF does not posses a classical transmembrane sequence and was initially thought to be released following mechanical injury to tissue to promote wound healing . However recent evidence suggests a non-classical endoplasmic reticulum-Golgi-complex independent pathway of secretion may exist for FGF-1 and FGF-2 [73,74]. FGF-2 is also thought to stimulate release of plasminogen activator and procollagenases from endothelial cells . The conversion to plasmin and collagenases from plasminogen and procollagenases respectively initiates breakdown of vascular basement membrane . This fragmentation of basement membrane then permits the formation of capillary sprouts via endothelial cell migration and proliferation into the wound site in response to VEGF and FGF release. Thus it is a combination of proliferation at the site of initial capillary sprouting and chemoattraction by mediators released in response to injury that drive the dynamic angiogenic process forwards. In addition, the advancing column of endothelial cells needs to concentrate MMP proteolytic activity to facilitate invasion of granulation tissue . The expression of cell surface receptors (integrins) with active MMPs (in particular MMP-2 and MMP-9) enable co-operation between the adhesive and proteolytic mechanisms of the endothelial cells that are invading the developing wound [76,77].
Upstream from this advancing column, a dynamic interaction between endothelial cells, matrix and cytokines heralds the onset of endothelial cell differentiation, basement membrane deposition and lumen formation. These new capillaries continue to grow and extend, eventually forming capillary arcades and networks. However like its surrounding matrix, remodelling of this vascular network is also required and involves the creation of large and small vessels, the recruitment of pericytes and adjustment of blood vessel density to meet nutritional needs. Pericytes, probably under the influence of PDGF and TGF, regulate endothelial cell proliferation, migration, differentiation, vascular branching and overall vascular maturity and survival [78-87],while the angiopoietins appear critical for overall vascular maturity and integrity [88-91]. In the mature adult vascular system, these recently discovered angiopoietins are essentially involved in the maturation, stabilisation and remodelling of blood vessels. The actions of the angiopoietins are specific to endothelial cells through tyrosine kinase with immunoglobulin and epidermal growth factor homology (Tie)-1 and Tie-2 receptors [92,93]. The angiopoietins use the Tie-2 receptor and although a functional ligand for the Tie-1 receptor remains unidentified, it is accepted that Tie-1 functions in controlling vascular endothelial cell integrity [90,94]. If angiopoietin 1 (Ang-1) and the Tie-2 receptor appear crucial for stabilisation in the normal vascular system, then by contrast it is Ang-2, representing a Tie-2 antagonist that is highly induced at sites of vascular remodelling, including in tissue repair [95,96]. Thus it seems likely that the disruption of the Ang-1/Tie-2 interaction by the dramatic up-regulation of Ang-2, in the presence of VEGF, is a prerequisite for normal angiogenesis .
Until recently angiogenesis was considered to be the sole mechanism of blood vessel formation in postnatal life. Vasculogenesis on the other hand refers to the development of the vascular system in the embryo and is due to the in situ differentiation of endothelial progenitor cells or angioblasts. However findings over the past 6 years require modification of this dogma with the identification of endothelial stem cells in the adult that have been shown to participate in blood vessel formation in both physiological and pathological states [97-105]. This unique component of 'angiogenesis' clearly requires further study in order to both fully unravel its role in both health and disease and for the development of novel therapeutic approaches to wound healing in the future.
Wound healing and CNV
The foregoing outlines our present understanding in relation to the sequence of events, with emphasis on angiogenesis, that is known to occur in wound healing. In general terms, an identical process occurs in what we clinically term CNV. Essentially all that differs from the classical wound healing model of the skin, is our area of specific interest, the macula. The main cellular players, their behaviour, the cytokines present and the evolving ECM response are virtually identical to that outlined above. Nevertheless we must recognise that molecular signals may vary from tissue to tissue and that cells such as endothelial cells can differ in different regions of the body . Histologic studies on post-mortem eyes with CNV have show that the neovascularization arises from the choroid and invades the subretinal space through Bruch's membrane and the RPE [107,108]. However, because these post-mortem CNV's had involuted due to the late stage of the disease in these eyes, it was difficult to draw firm conclusions pertaining to its pathogenesis. Obtaining globes with early CNV for study is extremely difficult due to their rarity  and it was only with the advent of submacular surgery that histological analysis of affected eyes at a much earlier stages of their development provided more useful information. For example, regardless of the etiology of CNV, both the cellular and extracellular constituents of CNV appear to be similar. This stereotypical uniformity of response again tends to suggest that what we are dealing with is in fact a wound healing response, characterised by a typical early inflammatory response and tissue formation, a prominent angiogenic response, followed by end stage involution/maturation of all involved elements, including the vascular component . From a cellular point of view, both RPE cells and macrophages are abundant in CNV [108-115]. However in post-mortem eyes exhibiting CNV involution, like tissue repair, macrophages do not appear to be a frequent feature [107,116], findings once again not only supporting the dynamic evolution of the CNV milieu, but also supportive of wound healing being the primary pathologic process.
In general, wound repair is a positive response and CNV formation is often clinically underdiagnosed [109,116] in age-related macular degeneration as the basal laminar deposit can mimic's Bruch's membrane and enable CNV development and maturation that can support both the RPE and photoreceptors. This form of wound repair with angiogenesis is desirable, however it is the subsequent protracted scarring response that irreversibly compromises the photoreceptors and RPE that highlights the need to treat CNV with therapies other than just anti-angiogenesis approaches. If we compare the CNV process more closely with wound healing, the similarities are striking. As in any wound there is both proliferation of cells at and recruitment of cells to the wound site . Once again it is surgically excised CNV that have provided much new information with respect to the growth factors and cytokines that are present at this earlier stage of CNV development. Surgical excision of CNV has demonstrated that both fibrin and fibronectin are major components of early CNV formation but are not seen in the later involutional stage [111-115]. Thus we have our provisional scaffold for migration of macrophages and RPE. Factors that are expressed by RPE and known to be present in CNV include TGF-β, FGF-1, FGF-2, and TNF-α, mediators that are abundant in both the inflammatory and granulation phase of wound healing [118-122]. The inflammatory response is mixed with both acute and chronic elements present [108,123]. Furthermore, and similar to tissue repair, the role of VEGF in CNV is incontrovertible and has a number of potential sources, including photoreceptors, Muller cells and of course RPE and macrophages [110,124-127]. However it is probably TNF-α expression by newly arrived macrophages that is responsible for the stimulation of IL-8 and MCP-1 by RPE . This initial autocrine/paracrine loop is completed with the recruitment of further macrophages by MCP-1 [128-130] while TNF-α expression by these CNV-associated macrophages also stimulates production of VEGF by RPE [120,131]. TNF-α expression may have an additional action on RPE by causing their migration on fibronectin, a component of the early 'CNV' ECM [111-115,132]. Furthermore the matricellular proteins SPARC, TN and TSP, present in CNV [133-136], have been implicated in a number of cellular functions, including phagocytosis, adhesion, proliferation and migration [137,138], functions that are all critically dependent on cell-ECM interaction during wound healing . Further evidence that CNV may represent a wound healing response is the finding of increased MMP and TIMP expression associated with both surgically excised specimens and in a laser-induced model of CNV [140,141]. Although the role of VEGF in the pathogenesis of CNV is unquestionable, the role of the angiopoietins in the angiogenic process is also being unravelled and similar to the wound repair situation, there appears to be a temporal and spatial relationship between VEGF and the angiopoietins [131,142,143]. Significant expression of both Ang-1 and Ang-2 has been demonstrated in surgically excised CNV secondary to a variety of etiologies [131,142,143]. Furthermore, these angiopoietins co-localized not just with endothelial cells, but also with macrophages and RPE. The co-expression of Ang-2 with VEGF in the more vascular regions of CNV may support a role of Ang-2 as a VEGF-dependent modulator of capillary structure and as a mediator of endothelial cell survival . Perhaps the expression of Ang-2, by blocking the stabilizing action of Ang-1 on the developing vasculature, permits further VEGF-driven angiogensesis [95,142]. However, as growth of the CNV complex nears completion, Ang-1-mediated Tie-2 activation predominates to allow maturation of the neovascular network . Thus, and again similar to wound healing, the expression of Ang-1 and Ang-2 is dependent on the stage of angiogenesis within the CNV. Several experimental models also provide insight into CNV from a wound healing perspective [145-152]. Essentially these models charter the development of the tissue repair response when the retina and choroid are 'wounded' with laser. Moreover, in recent years, the murine model of laser induced CNV has become the standard model in many laboratories to investigate the effects of altered gene expression in the retina on the development of CNV, thus providing information on the natural history of wound repair, as well as the effect of age on CNV and/or the genetic/therapeutic manipulation of the stem cell recruitment, angiogenic or inflammatory component of this healing response [149,150,152].
Based on our present knowledge, we can thus propose a model of CNV occurrence or submacular wound healing. It is likely that CNV or angiogenesis is just one component of a tissue repair response occurring secondary to a stimulus or 'injury' within the macular region. The insult that initiates wound healing may be a metabolic imbalance and/or hypoxia that may induce cellular damage within the outer segment of the retina or within the RPE-Bruch's membrane complex. Release of cytokines such as PDGF and TGF from these cells leads to the recruitment of macrophages. Expression of FGF-2, TGF, PDGF, IL-1 and TNF-α by these newly arrived macrophages and RPE leads to early matrix secretion and VEGF production by RPE. Meanwhile the synthesis and release of MCP by RPE amplifies the macrophage response. Additionally, migration by de-differentiated RPE within the provisional matrix occurs under the influence of TNF-α and heralds the onset of the tissue formation phase. Meanwhile, acting under the influence of VEGF, endothelial cells within the choriocapillaris de-differentiate and form capillary shoots and via the elaboration of MMPs, they can cross either a damaged or intact Bruch's membrane to negotiate the early matrix of the wound environment in order to negate the hypoxic environment of the diseased macula . Simultaneously, RPE, directed by TNF-α and other growth factors, themselves de-differentiate and proliferate, and together with choroidal fibroblasts, assume a wound repair phenotype and also migrate into the wound, aided by the production of MMPs. There, under the guidance of growth factors such as TGF-β, secretion of ECM and remodelling begin. Concurrently angiogensesis continues until a state of normoxia or hyperoxia exists, thereby switching off VEGF synthesis. This initiates vascular remodelling and maturation through pericyte recruitment probably through production of PDGF and angiopoietins leading to both a mature arterial and venous supply within the area. Finally, after many months, wound quiescence gives rise to a paucicellular cicatricial membrane beneath the macula.
In summary, the pathogenesis of CNV remains obscure and therefore effective therapy will continue to be elusive. At the cellular level both CNV and wound healing share an indisputable commonality. It therefore raises the prospect that CNV may be amenable to therapies other than just anti-angiogenesis approaches. Indeed one could argue that an anti-angiogenesis approach in a wound healing situation could in fact retard the reparative response and prolong disease. Ultimately, it is the scarring response that irreversibly damages photoreceptors so therapies that modify this response may help preserve or even rescue photoreceptors. This could include modulating the role of the inflammatory response [152,153] and/or RPE/fibroblasts . In addition, other elements of the vascular component, in the context of a tissue repair response, also merit attention including the later stages of angiogenesis such as the investment of blood vessels with pericytes, the process of vascular remodelling and whether the response of new vessels in CNV to anti-angiogenesis treatment could be influenced or modified by their stage of maturation . Furthermore, the presence of EPC's has recently been shown in CNV, thus providing a further avenue of therapeutic exploration [155-160]. In conclusion, in the context of wound healing, a better understanding of vessel growth, remodelling and maturation in CNV may advance, not only vascular therapies, but also non-endothelial approaches, and thus ultimately provide a better overall strategy in the management of CNV.
Supported by the British Council for the Prevention of Blindness (DK) and Dunhill Medical Trust (CS). The authors have no commercial or proprietary interest in any of the subject matter presented here.
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