Microvascular abnormalities of the retina, such as retinopathy of prematurity, macular degeneration and diabetic retinopathy are among the leading causes of non-traumatic blindness. These diseases are characterized by neovascularization that results from ischemic injury to retinal vessels, i.e., compensatory angiogenesis. In a mouse pup model of hypoxia-induced neovascularization of the retina, we plan to determine the role of the nucleoside adenosine in the compensatory angiogenesis. To quantify cell proliferation and the degree of neovascularization we will use cytochemistry and digital morphometry. Adenosine is released in increased amounts by hypoxic or damaged tissues, and has been shown to be a potent promoter of angiogenesis. We plan to test the following hypothesis: Adenosine released as a result of retinal ischemia produces proliferative effects in endothelial cells, and the resultant compensatory angiogenesis should be prevented or reduced by adenosine receptor antagonists. Thus, blocking using adenosine receptor antagonists will inhibit retinal neovascularization by blocking the effect of adenosine. In summary in the first phase of this project we will determine whether activation of adenosine receptors plays a mechanistic role in the development of compensatory angiogenesis of the retinal circulation. If our hypothesis is proven correct this small animal model of retinopathy will be used on the second phase of this project to (A) determine the adenosine receptors subtype that (e.g., A2A or A2B) that mediates angiogenesis, and (B) evaluate the action of novel adenosine receptor antagonists for therapeutic use. Successful accomplishment of this project will lead to a novel strategy to combat retinal pathologies associated with retinal neovascularization.
Our proposal will establish a causal relationship between endogenously released adenosine, acting via an adenosine receptor, and retinal neovascularization. Retinal neovascularization is the primary cause of diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. It is our intention to discover, develop, and commercialize an antagonist of adenosine (targeted to a specific receptor subtype, e.g., A2B) to slow or prevent retinal neovascularization.
