Selective Activation of the Prostaglandin E2Circuit in Chronic Injury-Induced Pathologic Angiogenesis

Abstract

Purpose.: Cyclooxygenase (COX)-derived prostaglandin E₂ (PGE₂) is a prevalent and established mediator of inflammation and pain in numerous tissues and diseases. Distribution and expression of the four PGE₂ receptors (EP1-EP4) can dictate whether PGE₂ exerts an anti-inflammatory or a proinflammatory and/or a proangiogenic effect. The role and mechanism of endogenous PGE₂ in the cornea, and the regulation of EP expression during a dynamic and complex inflammatory/reparative response remain to be clearly defined. Methods.: Chronic or acute self-resolving inflammation was induced in mice by corneal suture or epithelial abrasion, respectively. Reepithelialization was monitored by fluorescein staining and neovascularization quantified by CD31/PECAM-1 immunofluorescence. PGE₂ formation was analyzed by lipidomics and polymorphonuclear leukocyte (PMN) infiltration quantified by myeloperoxidase activity. Expression of EPs and inflammatory/angiogenic mediators was assessed by real-time PCR and immunohistochemistry. Mice eyes were treated with PGE₂ (100 ng topically, three times a day) for up to 7 days. Results.: COX-2, EP-2, and EP-4 expression was upregulated with chronic inflammation that correlated with increased corneal PGE₂ formation and marked neovascularization. In contrast, acute abrasion injury did not alter PGE₂ or EP levels. PGE₂ treatment amplified PMN infiltration and the angiogenic response to chronic inflammation but did not affect wound healing or PMN infiltration after epithelial abrasion. Exacerbated inflammatory neovascularization with PGE₂ treatment was independent of the VEGF circuit but was associated with a significant induction of the eotaxin-CCR3 axis. Conclusions.: These findings place the corneal PGE₂ circuit as an endogenous mediator of inflammatory neovascularization rather than general inflammation and demonstrate that chronic inflammation selectively regulates this circuit at the level of biosynthetic enzyme and receptor expression.