The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. Examples include proliferative retinopathies (PRs) such as retinopathy of prematurity and proliferative diabetic retinopathy, which are the leading causes of blindness in children and working-age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathologic hypervascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected toward the vitreous, suggesting that vasorepulsive forces operate in the avascular hypoxic retina. In the present study, we demonstrate that the neuronal guidance cue semaphorin 3A (Sema3A) IntroductionProliferative retinopathies (PRs) are traditionally perceived as disorders limited to the microvasculature because of the characteristic profuse and deregulated growth of retinal vessels. 1 The mechanisms by which neovessels grow toward the vitreous and fail to revascularize ischemic zones are thought to result from high concentrations of proangiogenic factors such as VEGF in the vitreous of PR patients. However, if such an explanation were sufficient, retinal glial cells (astrocytes and Müller cells) 2 and neurons 3 that produce vast amounts of growth factors under hypoxic conditions should retain vessels on the retinal surface and ensure revascularization of the retina proper. It is, therefore, compelling to hypothesize the presence of a vasorepulsive force originating from the significantly hypoxic avascular retina that repels neovessels away from the vaso-obliterated retina and grows toward the vitreous.Neurovascular cross-talk shapes vascular development but has received limited attention in the pathology setting. In PRs, evidence points to an early decline in the function of ischemic regions of the neural retina, as shown by multifocal electroretinogram (mfERG). 4,5 Throughout the vaso-obliterative phase of retinopathy, the local retinal environment is hostile to both vasculature and neurons. 6 After blood vessel degeneration, neurons are metabolically starved and undergo several adaptive cellular changes to counter the ischemic state of the tissue. 3,6 If adequate vascular supply is not reinstated in time to salvage deprived neurons, it is conceivable that these severely hypoxic cells may mount a repulsive front in an attempt to shunt metabolic resources away from the perishing ischemic tissue toward less affected regions of the retina. In the process, excessive production of VEGF 7 induces exaggerated neovascularization at the periphery of the ischemic and repulsive zones into the pre-retinal region (normally devoid of vasculature), because reestablishing a vascular network to neurons that are unsalvageable would be wasteful.Given their established role in influencing endothelial cell (EC) behavior, classic neuronal guidance cues may ...

Objective-Proinflammatory cytokines contribute to the development of retinal vasculopathies. However, the role of these factors and the mechanisms by which they elicit their effects in retina are not known. We investigated whether activated microglia during early stages of ischemic retinopathy produces excessive interleukin-1β (IL-1β), which elicits retinal microvascular degeneration not directly but rather by triggering the release of the proapoptotic/repulsive factor semaphorin-3A (Sema3A)