Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

soluble Eph-A2 receptor inhibited the migration and tube formation of retinal endothelial cells stimulated with either VEGF or ephrin-A1 ligand.

3.5.2Cyclooxygenase and the prostaglandins

The cyclooxygenase enzymes (COX1 and COX2) and their products, the prostaglandins, have emerged as potential mediators of pathological angiogenesis. Patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) have a reduced incidence of and mortality from colorectal cancer.89 NSAIDs are compounds that inhibit the activity of the COX enzymes. This provides a functional link between COX and angiogenic diseases, such as cancers. The therapeutic potential of COX inhibition has been tested for efficacy at inhibiting ocular angiogenesis. The non-selective COX inhibitors indomethacin, ibuprofen, and nepafenac, and the COX2selective inhibitor, rofecoxib, reduce retinal neovascularization in the mouse OIR model. 90-93

3.6Endogenous inhibitors of angiogenesis

Under physiological conditions, pro-angiogenic factors are counterbalanced by one or more endogenous anti-angiogenic factors. An increase in antiangiogenic factors may tip the scale in favor of vascular quiescence. Some of these factors are found within the eye, and targeting them for therapeutic application may lead to fewer side effects during treatment of retinal neovascularization.

3.6.1Pigment epithelium-derived factor

Pigment epithelium-derived factor, PEDF, is a member of the serpin (serine protease inhibitor) family of proteins.94 Although PEDF lacks serine protease inhibition activity, it is one of the most potent endogenous angiostatic factors. PEDF is more potent than angiostatin, endostatin, or thrombospondin-1, and inhibits the VEGF-induced migration of endothelial cells.95 Animal models demonstrate that PEDF immunoreactivity is higher in control animals than it is in animals experiencing ocular angiogenesis, and that the addition of exogenous PEDF or viral delivery of the PEDF gene can inhibit retinal angiogenesis and induce microvascular endothelial cell apoptosis.33,96-100 Furthermore, research has shown that rodents receiving a penetrating ocular injury after oxygen exposure exhibit less retinal

neovascularization. The angiostatic effect of the penetrating ocular injury is consistent with an increase in PEDF mRNA and protein expression.101,102

Administering recombinant PEDF leads to a significant inhibition of retinal

neovascularization in the mouse OIR model.97 In a recent phase I clinical trial, adenoviral-delivery of PEDF led to an inhibition of neovascular agerelated macular degeneration. The results of this phase I clinical trial suggest that ocular gene transfer is a rational approach for the treatment of ocular proliferative disorders.103

3.6.2ECM-related inhibitors of angiogenesis

Endostatin is an endogenous fragment of collagen type XV and collagen type XVIII that has anti-angiogenic activity. Viral-mediated delivery of endostatin prevents retinal neovascularization in the mouse OIR model.98 May and colleagues have proposed that endostatin-like proteins (ELPs) may play a self-limiting role in ROP-associated neovascularization. ELPs are absent at the beginning of the neovascular response, but increase over time, persisting as the vessels regress.104

Angiostatin is an endogenous fragment of plasminogen that possesses

anti-angiogenic activity. Treating mice with angiostatin leads to a significant reduction in the development of OIR.105,106

Thrombospondin-1 (TSP-1) is an anti-angiogenic ECM glycoprotein. If TSP-1 is injected immediately after oxygen treatment, rat retinal neovascularization is reduced by 48%.107 Similarly, synthetic peptides derived from TSP-1 that contain either the TGFβ activating domain or the heparin binding domain were shown to have an inhibitory effect on retinal neovascularization.107 In vivo, the TSP-1 peptide containing the heparin binding domain was shown to be the most potent inhibitor of neovascularization. VEGF presentation to the VEGFR is mediated by the binding of VEGF to heparin on the surface of endothelial cells.108 It is hypothesized that TSP-1, by binding heparin, effectively prevents the interaction between VEGF and heparin, serving to reduce VEGF’s activation of its receptor.

3.6.3Proteolytic inhibitors of angiogenesis

Urokinase plasminogen activator (uPA) cleaves plasminogen, an inactive serine protease precursor, to yield the active protease plasmin. Plasmin has broad specificity and cleaves a variety of proteins, including several important ECM components.109 Plasmin is also able to activate several matrix metalloproteinases (MMPs),110 proteolytic enzymes responsible for the degradation of the vascular basement membrane. Therefore, uPA initiates a cascade culminating in the degradation of the basement membrane. This permits the extravasation, migration, proliferation, and tube formation of endothelial cells undergoing angiogenesis. Endogenous plasminogen activator inhibitor (PAI-1) suppresses uPA activity. In the rat

OIR model, intravitreal injection of recombinant PAI-1 reduced retinal neovascularization by 52% at the highest dose tested.111 Endogenous tissue inhibitors of metalloproteinases (TIMPs) inhibit MMP activity. Targeting PAI-1 or the TIMPs, alone or in combination, offers an attractive antineovascular strategy, since these molecules are endogenous to the retina.

4.CONCLUDING REMARKS

Retinopathy of prematurity is a disease characterized by abnormal retinal angiogenesis. The development and utility of the rodent OIR models have contributed much of the information currently known about physiological and pathological retinal capillary growth. Because of the ease of their manipulation, rodent OIR models have provided a commonly used means to study the angiogenic process. In addition, the rodent eye is readily accessible, and its vasculature is easy to visualize and assess. Rodent OIR models have shed light on the cellular and molecular pathogenesis and pharmacological treatment of ocular, as well as non-ocular, vasoproliferative disorders. The continued refinement of the models and the knowledge gained through their use will aid the development of therapies to alleviate neovascular diseases of the human eye.

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