The Role of COX-2 in Pathological Ocular Angiogenesis
Yanni, Susan Elizabeth
Pathological ocular angiogenesis, or ocular neovascularization (NV) is a central feature of retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and age-related macular degeneration (AMD). In the developed world, these diseases are the leading causes of blindness in infants, working-age individuals, and the elderly, respectively. As of today, there are two FDA-approved angiostatic agents being used to treat conditions characterized by ocular NV. Both angiostatic agents inhibit vascular endothelial growth factor (VEGF), the principle growth factor mediating ocular NV. Although VEGF-centric therapies reduce NV, they do not completely eliminate it. In order to more effectively prevent and/or treat these conditions, a more thorough understanding of the key players involved in the angiogenic cascade is needed. One enzyme that holds promise for therapeutic intervention is cyclooxygenase-2 (COX-2). We examined the involvement of COX-2 and COX-2-derived prostanoids in order to 1) understand their role in ocular angiogenic disease, and 2) develop more specific therapeutic targets for diseases comprised of an angiogenic component. We have shown that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the activity of COX, significantly reduced the severity of NV in an animal model or oxygen-induced retinopathy (OIR). This anti-angiogenic effect was likely due to inhibition of VEGF-induced endothelial cell proliferation and tube formation. Furthermore, genetic deletion of COX-2 significantly reduced hypoxia-induced VEGF production by Müller cells. This effect was mediated by one of the five COX-derived prostanoids, PGE2. Additional experiments confirmed the role of PGE2 and, more specifically, the EP4 receptor, in angiogenic Müller cell and endothelial cell behaviors. Importantly, EP4 antagonism significantly reduced VEGF production by hypoxic Müller cells, VEGF-induced proliferation and tube formation in endothelial cells, and the severity of NV in rodent models of OIR and laser-induced choroidal NV (LCNV). Our findings are significant because they demonstrate that the EP4 receptor affects the ocular angiogenic cascade at more than one point, with the potential to be a powerful and effective therapeutic target for angiogenic diseases of the eye and other tissues.