kininiogen in Ocular angiogenesis-mediated disorders

Retinal and choroidal angiogenesis are major causes of vision loss, and the pathogenesis of this angiogenesis process is still unclear. However, several key steps of the angiogenic cascade have been elucidated. In retinal angiogenesis, hypoxia is the initial stimulus that causes upregulation of various factors, which results in endothelial cell proliferation and migration. Although the steps of choroidal angiogenesis seem to be similar to those of retinal angiogenesis, there are some major differences between these two processes. Several anti-angiogenic approaches are being developed in animal models as well as in clinical trials to prevent ocular angiogenesis by blocking the key steps in the angiogenic cascade. Intact Kininogen (HK) is known to promote inflammation, complement activation, release bradykinin (permeability factor), and activate coagulation; more recently, it was shown to stimulate angiogenesis that might be mediated by its multiple mediators. These characteristics of HK suggest that its blockade might have significant benefits in the complex etiology of retinal and choroidal neovascularization. Studies from our laboratories have documented the antiangiogenic activity of cleaved HK (HKa) and its domain 5 (D5) to be due to their zinc-dependent binding to uPAR, which initiates signaling that interferes with the cell cycle and the proangiogenic activity exerted through the activation by intact HK. We have demonstrated that D5 or certain of its constituent peptides inhibit angiogenesis. We hypothesize that intact HK is proangiogenic and functions by liberating bradykinin among other mechansims and a monoclonal antibody (mAb C11C1) that interferes with the binding of HK to cell receptors would inhibit ocular angiogenesis. Based on our findings, we hypothesize that mAb C11C1 and D5 will inhibit angiogenesis in experimental models of retinal neovascularization. This novel strategy might alter the pathogenesis of retinal angiogenesis and provide an alternative pharmacological approach for ocular angiogenesis-mediated disorders.