Ординатура / Офтальмология / Английские материалы / Ocular Periphery and Disorders_Dartt, Bex, Amore_2011

cultured ECs. It also inhibits NV in vivo. Canstatin is a 24-kDa fragment of the type IV collagen a-chain. It also inhibits EC proliferation and tube formation. The mechanism of action appears to involve phosphoinositide 3-kinase/ protein kinase B (PI3K/Akt) inhibition and depends on signaling events transduced through membrane-death receptors. Tumstatin, a 28-kDa fragment of the type IV collagen a3 chain, also has anti-angiogenic activity.

Therapy

Identifying and adequately treating the underlying cause of corneal NV is critical. Therapies for corneal NV may range from antimicrobial therapy for infectious keratitis to systemic immunosuppression for autoimmune diseases such as ocular cicatricial pemphigoid. Some of the established and investigational medical and surgical treatments for corneal NV are discussed below.

Medical Treatments

Anti-inflammatory compounds, such as steroids, have a long history of use for the suppression of inflammation and associated angiogenesis. The anti-angiogenic effects of steroid treatment are likely secondary to their antiinflammatory actions and include inhibition of chemotaxis and cytokine synthesis. Steroids have also been shown to inhibit vascular EC proliferation and migration. Unfortunately, the side effects of these compounds make long-term administration difficult in some patients. Moreover, their role in corneal NV that is not associated with inflammation is limited.

Advances in our understanding of the mechanisms underlying ocular NV has led to the identification of new pharmacologic targets. Given the key role of VEGF in NV of the eye, attention has been directed to developing drugs that will counteract the activity of this factor. Bevacizumab is an anti-VEGF antibody that binds to all VEGF isoforms. This molecule inhibits VEGF-receptor interactions and in this way, blocks all VEGF actions. It is currently approved by the FDA to treat metastatic colorectal cancer. It has also been tested for the treatment of wet (neovascular) age-related macular degeneration (AMD). Ranibizumab is another anti-VEGF antibody that has been approved for use in the eye to treat wet AMD. Bevacizumab treatment of corneal NV has gained popularity since the successful use of this molecule to treat choroidal NV. Subconjunctival injection as well as topical application of this molecule has also been used with promising results to treat herpes simplex virus (HSV) keratitis, recurrent pterygia, rejection of corneal grafts, and Stevens–Johnson syndrome. However, data on these treatments are limited, and adverse effects such as loss of epithelial integrity and progression of thinning have been reported in a small number of patients.

Further investigation is required to establish efficacy, adequate dosing, and safety in the different clinical scenarios that present with corneal NV.

Other forms of anti-VEGF therapy are currently undergoing clinical trials. One example is VEGF TRAP, a highaffinity VEGF antagonist designed to bind and neutralize VEGF in the circulation and within tissues. It binds to all isoforms of VEGF and to placental growth factor, which is a related pro-angiogenic factor. SIRNA-027, another anti-VEGF therapy, is a short interferon RNA designed to downregulate VEGFR-1 expression. PKC412 is an orally administered tyrosine kinase inhibitor that binds to the intracellular, enzymatically active domain of the VEGF receptor and prevents phosphorylation and activation of the VEGF signaling cascade. Some of these compounds may be available for use in the near future.

Surgical Treatment

One surgical approach for the treatment of corneal NV is laser therapy. The use of laser photocoagulation with a 577-nm yellow dye for the treatment of established corneal NV has been investigated. The effectiveness of this technique has been tested in clinically significant corneal NV resistant to medical therapy both before and after PK. Some reduction of corneal NV can be achieved; however, the benefit of laser photocoagulation prior to high-risk keratoplasty is unclear, and this technique does not appear to be useful for treating extensive corneal NV.

An alternative to laser occlusion is fine-needle diathermy. This procedure is easy to perform, requiring only a 10-0 nylon suture and a unipolar diathermy unit. It produces occlusion of 50–100% of corneal NV and has been show to moderately benefit visual acuity in a series of 17 patients.

Photodynamic therapy is currently used to treat choroidal NV. In this technique, a photo-sensitizer selectively accumulates in new vessels and is subsequently activated by a laser beam. This technique is currently under investigation in animal models of corneal NV.

Finally, in some cases, conjunctival, limbal, or amniotic membrane transplantation may be required to restore the ocular surface. Conjunctival autograft and allograft transplantation have been shown to decrease corneal NV. Amniotic membrane has anti-angiogenic properties as well. Limbal autograft transplantation has been successful in cases of stem cell deficiency and conjunctival metaplasia. This technique not only treats the stem cell deficiency and decreases the angiogenic stimulus from chronic ulceration, but also directly inhibits vascular ECs.

No ideal treatment is currently available for corneal NV. However, significant progress in the understanding of corneal angiogenesis has opened a new field of investigation that may lead to the development of novel therapeutic agents for the treatment of this condition.

See also: Concept of Angiogenic Privilege.

Further Reading

Ambati, B. K., Nozaki, M., Singh, N., et al. (2006). Corneal avascularity is due to soluble VEGF receptor-1. Nature 443: 993–997.

Azar, D. (2006). Corneal angiogenic privilege: Angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing. Transactions of the American Ophthalmological Society 104: 264–302.

Chang, J. H., Gabison, E. E., Kato, T., and Azar, D. T. (2001). Corneal neovascularization. Current Opinion in Ophthalmology 12: 242–249.

Cursiefen, C., Chen, L., Saint-Geniez, M., et al. (2006). Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proceedings of the National Academy of Sciences of the United States of America 103: 11405–11410.

Dorrel, M., Uusitalo-Jarvinen, H., Aguilar, E., and Friedlander, M. (2006). Ocular neovascularization: Basic mechanisms and therapeutic advances. Survey of Ophthalmology 52: 3–19.

Ma, D. H., Chen, J. K., Zhang, F., et al. (2006). Regulation of corneal angiogenesis in limbal stem cell deficiency. Progress in Retinal and Eye Research 25: 563–590.

Zhang, S. X. and Ma, J. X. (2007). Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Progress in Retinal and Eye Research 26: 1–37.

Glossary

Alloimmunity – A condition in which the body gains immunity, from another individual of the same species, against its own cells.

Aniridia – Congenital disorder characterized by the abnormal deficient development of the iris and associated with corneal angiogenesis and poor vision.

Atopic keratoconjunctivitis (AKC) – Allergic conjunctivitis where the conjunctiva is red and swollen. Untreated, AKC can progress to ulceration, scarring, cataracts, keratoconus, and corneal vascularization.

Hemangiogenesis – It pertains to the specific growth of blood vessels.

Limbus – The edge of the cornea where it joins the conjunctiva and the sclera.

Lymphangiogenesis – It pertains to the specific growth of lymphatic vessels.

Neovascularization – Formation of new blood and lymphatic vessels.

Perforating keratoplasty – Corneal transplant with replacement of all layers of the cornea, but retaining the peripheral cornea.

Light, the substrate of vision, is required to transverse the full diameter of the eye globe and reach retinal photoreceptors giving rise to the intricate biophysical phenomenon of sight. The cornea, interfacing the outer world and the intra-ocular tissues, serves as an entry window through which light comes into the eye. Avascularity and optical transparency are directly related and a requirement for optimal vision. The absence of vessels in the cornea is also one of the pillars of corneal immune privilege, an important physiological phenomenon that is associated with the maintenance of corneal clarity and responsible for the high success rate of corneal transplants. The growth of blood and lymphatic vessels into the normally avascular cornea (neovascularization) is considered pathological as it impairs the passage of light resulting in severely deteriorated vision or complete corneal blindness, which together afflict over 200 million people worldwide.

The absence of vascular structures in the cornea has been known for over 1000 years. But only recently, advances in molecular biology have led to improved

understanding of the homeostatic mechanisms underlying such phenomenon. The absence of vasculature (blood and lymphatic vessels) in the cornea is remarkably intriguing given the highly vascularized nature of the neighboring tissues such as the ocular conjunctiva. The abrupt and precise delineation of the limbal vasculature (Figure 1) suggests that corneal avascularity is an active process in which endogenous proand anti-angiogenic mechanisms are in harmony and that these molecular modulators of angiogenesis are differently expressed in these interfaces between the cornea and its neighboring tissues preventing the blood and lymphatic vessels from invading the avascular cornea.

Corneal Histology

Histologically, the cornea is comprised of five layers (Figure 2). The epithelial layer coats its outermost surface and is composed of a thin nonkeratinized squamous stratified epithelium (only a few cells thick). Unlike the stratified squamous epithelium of the epidermis, that contains indented dermal papillae, the corneal epithelium lays flat on a thick basement membrane called Bowman’s membrane. The subjacent layer of the cornea, its stroma or substantia propria, is formed by tightly packed collagen fibers that are uniquely organized in a parallel fashion affording the cornea its crystal clear disposition. The corneal stroma is devoid of blood and lymphatic vessels and is populated by fibroblasts. In addition to fibroblasts, the substantia propria is also endowed with a heterogeneous population of cells including bone-marrow-derived cells, and antigen presenting dendritic cells, most of which, under normal physiological conditions, are still immature and remain quiescent. Descement’s membrane, a thick lamina propria, separates the corneal stroma from its innermost cellular layer: the corneal endothelium, which consists of a single layer of low cuboidal cells. The corneal endothelium is critical for water homeostasis as it actively transports excess fluid from the corneal stroma into the anterior chamber. This peculiar histological organization of the cornea with a thin epithelium layer and an active endothelium allows oxygen from the room-air and nutrients from the aqueous humor to diffuse through its full thickness. Because the loss of avascularity in the cornea results in impaired light transmission and poor vision, these unique histological features evolved over time and bestowed the cornea with the ability to remain viable and clear in the absence of a direct blood supply.

Figure 1 Photograph of the human limbus showing the abrupt termination of the conjunctival vasculature in the interface between the cornea (C) and the conjunctiva (CJ). Dotted line delineates the limbus.

Corneal Avascularity and Optical Clarity

The visual impairment associated with the loss of corneal avascularity is not only related to the physical obliteration caused by the opaque vessels within the visual field. Corneal neovascularization also reduces visual acuity because the infiltrating vasculature disrupts the tightly packed collagen bundles eliciting opacities, especially in areas surrounding the newly formed vessels. Vascular leakage and edema, usually associated with inflammatory neovascularization, overwhelms the endothelium drainage capacity, creates fluid accumulation, disrupts corneal clarity, and perturbs light transmission. Additionally, the neovascular corneas may also have diminished transparency due to lipid deposits. This is observed in vascularized corneas following corneal herpetic infections. Altogether, these observations speak of the tight correlation that exists between corneal avascularity, corneal transparency, and optimal optical performance.

Endogenous Anti-Angiogenic

Mechanisms

The molecular homeostatic mechanisms supporting the lack of vessels in the cornea were unknown until recently. Long ago, it was postulated that corneal avascularity was a

EPI

BM

STR

DM

END

Figure 2 Photomicrograph of the human cornea stained with H&E showing its histological layers. The epithelial layer (EPI) overlaying Bowman’s membrane (dotted line). The corneal stroma (STR) displaying its tightly packed parallel collagen fibers. Descement’s membrane (DM) interfacing the substantia propria and the corneal endothelium (END).

passive process. It was thought that the cornea was avascular simply because pro-angiogenic forces were not present. It is quite intriguing, however, that the avascular cornea is surrounded by extremely vascularized tissues, such as the ocular conjunctiva and iris. Because pro-angiogenic factors are a requirement for endothelial cell survival one may postulate that the cornea must be armed with angiostatic capabilities in order to counteract the constant angiogenic stimuli that derives from the adjacent vascular beds. This alternate hypothesis has challenged the previous beliefs, became accepted as a working hypothesis, and still stands as a paradigm of modern vascular biology. Currently, it is well known that corneal avascularity is an extremely active phenomenon, requiring an exact balance between proand anti-angiogenic forces, and not the mere absence of pro-angiogenic stimulation.

Extrinsic and intrinsic mechanisms have been proposed to underlie the absence of blood and lymphatic vessels in the cornea. The aqueous humor, fluid that circulates through the anterior chamber of the eye, has been regarded as a major extrinsic inhibitor of corneal angiogenesis. It contains several soluble angiostatic molecules including heparan sulfate proteoglycans. Because vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), the foremost studied angiogenic factors, bind to

these glycoproteins with relative high affinity, it has been proposed that the aqueous humor sequesters VEGF and bFGF from the cornea into the anterior chamber. However, it is important to bear in mind that not all isoforms of VEGF, like VEGF121, shown to be expressed in the cornea, bind heparan sulphate. This suggests that additional mechanisms are in place to secure corneal avascularity. In reality, it has long been suggested that corneal avascularity is a phenomenon supported by a redundant system. Additional factors contributing to corneal avascularity include the intrinsic synthesis of angiostatic molecules. It has been shown that the cornea expresses several of these anti-angiogenic factors, like angiostatin, endostatin, thrombospondins (TSPs), interleukin-1 receptor antagonist, pigmented epithelium-derived factor (PEDF), non vascular VEGF receptor-3 and soluble VEGF receptor-1.

The current paradigm of intrinsic angiostatic mechanisms in the cornea derived from the clinical observation that corneal epithelial dysfunction was often associated with neovascularization. This suggested that the antiangiogenic powers of the cornea resided primarily in its epithelial layer. In fact, most of the anti-antiangiogenic factors identified in the cornea have been localized primarily to the corneal epithelium.

Angiostatin, a by-product of plasminogen, was first isolated in 1994. Its angiostatic effect was initially demonstrated in a cancerous tumor growth and metastasis model. Mechanistically, angiostatin is thought to inhibit ATP synthase activity, block endothelial cell migration and proliferation and also cause vascular endothelial cell apoptosis. Angiostatin has been detected in healthy human corneal extracts and it has been shown that human corneal epithelium in culture is capable of converting exogenous plasminogen into its angiostatic by-product. Angiostatin has also been implicated in the maintenance of angiogenic privilege in the normal cornea and after wound healing.

Endostatin was first described in 1997. It is a proteolytic fragment of the caroboxyterminus of collagen XVIII. It has been portrayed as a potent inhibitor of angiogenesis and tumor growth. Collagen XVIII is a component of the basement membrane ubiquitously expressed and it also has been shown to exist in ocular tissues. Immunohistochemical studies have localized collagen XVIII and endostatin to the corneal epithelium, principally in the basal epithelium. Endostatin has been shown to block VEGFinduced phosphorylation of VEGFR-2 and inhibit endothelial cell proliferation and migration. The synthesis of endostatin in the cornea is upregulated during injury and has been shown to inhibit injury-induced corneal neovascularization. Although endostatin has been shown in the uninflammed cornea, mice deficient in collagen XVIII have normal avascular corneas, suggesting that endostatin is only one of many factors contributing to the maintenance of corneal avascularity.

TSP-1 and -2 are potent anti-angiogenesis protein. TSP-1 directly inhibits the migration and survival of endothelial cells by activation transforming growth fac- tor-beta (TGF-b). TSP-2 inhibits vascular endothelial cell proliferation independently of TGF-b activation. Both molecules have been detected in the mouse and human corneas under normal physiological conditions. Exogenous administration of TSP-1 and/or -2 have been associated with diminished suture-induced corneal angiogenesis. However, the systemic ablation of TSP-1 and -2 was not associated with spontaneous angiogenesis in the cornea, suggesting that alternate redundant angiostatic mechanisms are operative in the cornea.

Interleukin (IL)-1 receptor antagonist, a key modulator of IL-1 activity, was shown to be expressed in the normal human cornea. It was localized to the corneal epithelium and some stromal fibroblasts. In a mouse model of sutureinduced corneal neovascularization IL-1 receptor antagonist was shown to have anti-angiogenic properties and its exogenous administration was also associated with diminished infiltration of inflammatory cells into the cornea. IL-1 receptor antagonist deficiency in mice had no bearing in corneal avascularity, once again implying that corneal avascularity is secured by a multifactorial and redundant system.

VEGFR-3, normally expressed in lymphatic endothelial cells (LECs), corneal dendritic cells, and macrophages, was shown to be ectopically expressed in corneal epithelial cells of human and mice. These ectopic receptors have been shown to work as an inhibitor of injuryinduced corneal angiogenesis in mice.

Since its discovery in 1993, soluble VEGFR-1 (sVEGFR-1) has been extensively studied as a powerful inhibitor of VEGF-induced angiogenesis. It has been implicated in several pathological states, including preeclampsia, sepsis, arthritis, and cancer. Interestingly, VEGF, a powerful driver of angiogenesis, is expressed in the normal avascular cornea. Recently, it has been shown that sVEGFR-1 is co-expressed by the corneal epithelium serving as a VEGF manacle. Because the systemic ablation of VEGFR-1 gene is not compatible with survival, corneal specific deletion of VEGFR-1 was employed in mice and led to spontaneous corneal neovascularization. sVEGFR-1 is considered to be singularly essential for maintaining corneal avascularity of the uninjured cornea. The expression of sVEGFR-1 in the cornea was also shown to be conserved among mammals, including humans. One exception is the Manatee, whose cornea is spontaneously vascularized and lacks sVEGFR-1 expression. A similar splice variant of VEGFR-2, sVEGFR-2, was recently identified and described as the first specific endogenous inhibitor of lymphangiogenesis. In the cornea, sVEGFR-2 was shown to be singularly essential to maintaining the cornea devoid of lymphatic vessels, as its genetic deletion cause spontaneous invasion of lymphatic, but not blood vessels into the cornea.

Loss of Corneal Avascularity

Corneal neovascularization occurs when the precise equilibrium between proand anti-angiogenic forces is disrupted. The loss of corneal avascularity is pathological. Several ocular disorders are hallmarked by corneal neovascularization. These neovascular disorders of the cornea range from benign contact lens-associated neovascularization to congenital and hard to manage ocular anomalies such as aniridia.

Extended contact lens wear may induce neovascularization because the associated hypoxia triggers a steep rise in VEGF expression, overwhelming the natural antiangiogenic barriers. Other corneal disorders are coupled with pathological angiogenesis because of direct damage to the corneal epithelium. Corneal trauma, such as corneal abrasions or chemical (alkali) burn of the ocular surface, infections (herpetic keratitis), immune diseases such as atopic keratoconjuctivitis or rheumatoid arthritis, limbal cell deficiency, or congenital anomalies such as aniridia are all associated with the loss of avascularity. These clinical entities commonly require surgical management, like refractive surgery or perforating keratoplasty, both of which are negatively impacted by the preexistence of vessels in the cornea. This represents a significant clinical predicament and speaks of the critical nature of unveiling molecular targets that may be manipulated to treat the aberrant and disordered growth of vessels into the cornea.

Immune Privilege of the Avascular

Cornea

The absence of blood and lymphatic vessels in the cornea is known to play a critical role in maintaining its immune privilege, but other immune-protective mechanisms have been described. One such mechanism is referred to as anterior chamber-associated immune deviation (ACAID). ACAID is regarded as the ability of antigen-presenting cells (APCs) and antigens from anterior chamber-associated tissues (i.e., cornea) to directly enter the blood circulation through the trabecular meshwork homing to the spleen where immune tolerance is induced. Additionally, tissues from the anterior segment of the eye have been reported to express Fas-ligand which induces apoptosis in activated immune cells (Fas-receptor positive), thus protecting the cornea from damage by stimulated lymphocytes. These mechanisms are thought to collectively downregulate inflammation in the cornea, thereby preserving corneal clarity which is essential for optimal vision. Corneal avascularity is therefore one factor of several redundant active mechanisms aimed at preserving corneal transparency and optical light transmission.

Corneal Transplant and Avascularity

In 1905, ophthalmologist Edward Zim performed the first corneal transplant in a human subject. Since then, corneal transplants have become the most common type of solid tissue transplantation in the world. Nearly 46 000 corneal transplants are preformed yearly in the US. In addition to being the most prevalent, corneal allograft transplantation, it is also the most successful intervention among other commonly transplanted organs. However, the long-term outcome of this intervention is greatly influenced by pre-operative risk factors, with corneal neovascularization (high-risk group) being an important negative predictor of corneal allograft survival. While graft survival is approximately 90% in the low-risk group (no pre-operative inflammation or neovascularization), these numbers are drastically reduced to roughly 35% in the high-risk group. Recent studies targeting corneal angiogenesis with VEGF-A binding molecules (VEGF-trapW) demonstrated that allograft survival is inversely related to the amount of neovascularization in the murine corneal transplantation model corroborating the aforementioned epidemiological observations. The loss of corneal avascularity is therefore a significant clinical quandary.

The surgical procedures used in corneal allograft transplantation require delicate techniques to prevent adverse inflammatory reactions which may compromise outcome. The corneal graft is attached to the recipient’s ocular surface with the placement of small sutures. Paradoxically, in a vastly employed injury model of corneal angiogenesis, similar intrastromal sutures are used as a method of eliciting blood and lymphatic vessel growth. Because suture placement is a requirement for corneal transplantation as well as a pro-angiogenic stimulus, it is critical to understand the molecular underpinnings related to the growth of blood and lymphatic vessels into the cornea, so potential molecular targets could be identified and manipulated to promote corneal avascularity, optimal optical performance, and prevent corneal blindness.

Corneal Alymphaticity and Allograft

Rejection

Because the growth of blood and lymphatic vessels into the cornea are intimately intertwined, the individual contribution of each of these vasculatures to the fate of corneal allografts is not clearly understood. However, recent evidence suggests that the growth of lymphatic vessels into the cornea may be more tightly associated with loss of corneal immune privilege and critical for corneal allograft rejection than corneal hemangiogenesis.

Substantial progress in the study of corneal lymphangiogenesis has taken place since the discovery of VEGFR-3

and its ligands VEGF-C and –D. The identification of specific cellular makers preferentially expressed by LECs, such as LYVE-1, Prox1, and Podoplanin, has also propelled great advances to the field of lymphangiogenesis.

Corneal lymphangiogenesis generally occurs after corneal injury and inflammation, which in turn is associated with increased levels of VEGF-C. The newly formed corneal lymphatic vessels give rise to an afferent route through which corneal transudate and APCs are carried from the interstitial space into the lymphatic system and later back into the blood circulation. This drainage pathway becomes extremely deleterious in the context of corneal transplantation. Under these circumstances, the alternative route bypassing the standard outflow pathway (i.e., trabecular meshwork in the anterior chamber) allows for antigens from the donor cornea to escape through the lymphatic system and into the draining lymph node where a graft rejection reaction is initiated. The significance of this alternate drainage pathway to corneal alloimmunity and graft rejection has been portrayed in studies demonstrating that removal of cervical lymph nodes significantly increases the transplant survival rates in the low-(noninflamed, nonvascularized) and high-risk (neovascularized) groups. Together, these observations suggest that improved molecular understanding of corneal lymphangiogenesis, as well as the identification of endogenous compounds with the ability to uncouple lymphangiogenesis from hemangiogenesis would shed light into our current understanding of allograft rejection and potentially unveil therapeutic targets to enhance the survival of corneal allograft.

The Avascular Cornea as an Angiogenesis

Study Platform

The avascular disposition and its ready accessibility have made the cornea an important platform for the study of angiogenesis allowing scientists to test the pro-and/or anti-angiogenic effects of several compounds in vivo. Numerous assays have been developed to study angiogenesis modulation utilizing the cornea. Direct intra-stromal injection of angiogenesis compounds have been performed in the mouse, rat and rabbit cornea. Models in which a transient chemical (alkali), physical (scraping), or thermal (cautherization) injury are incurred to the cornea to provoke an angiogenic response have been widely used. Prolonged injury of the cornea has been achieved with intra-stromal suture placement. The insertion of a small pellet containing pro-angiogenic molecules has also been described and termed corneal micropocket assay. The cornea stroma has even been utilized for the implantation of tumor cells. The reliability of these models and the easy visualization of corneal vessels have placed the cornea in

the forefront of discovery and in vivo testing of drugs for the treatment of disorders hallmarked by aberrant angiogenesis, particularly cancer. The ability of analyzing these molecules in vivo provides valuable insight regarding the angio-modulatory effects of such compounds.

Conclusions

Avascularity of the cornea is intimately related to optical transparency and optimal vision. Hence, the loss of corneal avascularity is pathological and often results in impaired vision or corneal blindness. A precise balance between proand anti-angiogenic factors is essential to maintain the avascular disposition of the cornea. Even though it is well known that corneal immune privilege is a function of a constellation of factors, the absence of blood and lymphatic vessels in the cornea has proven to be one of its most important underlying mechanisms. A more precise understanding regarding the individual contribution of blood and lymphatic vessel growth to corneal alloimmunity is needed. The cornea, given its avascular nature and accessibility, is an ideal the platform for the in vivo testing of angiogenesis modulators.

See also: Corneal Angiogenesis; Tear Drainage.

Further Reading

Albuquerque, R. J. C., Hayashi, T., Cho, W. G., et al. (2009). Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth.

Nature Medicine 15: 1023–1030.

Ambati, B. K., Nozaki, M., Signh, N., et al. (2006). Corneal avascularity is due to soluble VEGF receptor-1. Nature 443: 993–997.

Azar, D. T. (2006). Corneal angiogenic privilege: Angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis).

American Ophthalmological Society 104: 264–302.

Cursiefen, C. (2007). Immune privilege and angiogenic privilege of the cornea. Chemical Immunology and Allergy 92: 50–57.

Cursiefen, C., Chen, L., Saint-Geniez, M., et al. (2006). Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proceedings of

the National Academy of Sciences of the United States of America

103: 11405–11410.

Folkman, J. (2007). Angiogenesis: An organizing principle for drug discovery? Nature Reviews Drug Discovery 6: 273–286.

Hirsch, E., Irikura, V. M., Paul, S. M., et al. (1996). Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proceedings of the National Academy of Sciences of the United States of America 93: 11008–11013.

Krachmer, J., Mannis, M., and Holland, E. (2004). Cornea. Amsterdam: Mosby.

Lawler, J. (2000). The functions of thrombospondin-1 and -2. Current Opinion in Chemical Biology 12: 634–640.

O’Reilly, M. S., Boehm, T., Shing, Y., et al. (1997). Endostatin:

An endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277–285.

O’Reilly, M. S., Holmgren, L., Shing, Y., et al. (1994). Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell

79: 315–328.

Spencer, W. H. (1996). Ophthalmic Pathology: An Atlas and Textbook.

Philadelphia, PA: W.B. Saunders.

Whitcher, J. P., Srinivasan, M., and Upadhyay, M. P. (2001). Corneal blindness: A global perspective. Bulletin of the World Health Organization 79: 214–221.

Yamagami, S., Dana, M. R., and Tsuru, T. (2002). Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation. Cornea 21: 405–409.