Neurons and guidance cues in retinal vascular diseases

Retinal vasculopathies such as diabetic retinopathy (DR), retinopathy of prematurity (ROP), and age-related macular degeneration (AMD) are the most common causes of vision loss in the industrialized world. According to the National Eye Institute, 7.7 million Americans are affected by DR, an additional 10 million have AMD, and of the 3.9 million infants born annually in the U.S., ~15 000 are affected to some degree by ROP. In wet AMD, unchecked proliferation of choroidal vessels leads to photoreceptor compromise and vision loss. In ischemic retinopathies such as ROP and DR, degeneration of retinal vessels is followed by misguided pathological neovascularization. Recent studies on DR, ROP and AMD have revealed the paramount role for neurons and neuronal guidance cues in disease progression [1-6]. During retinal embryogenesis, coordinated interplay between neurons, blood vessels and immune cells is critical for proper retinal development. Although neurovascular and neuroimmune crosstalk shapes vascular development in the retina, it has received limited attention in disease etiology. A better understanding of this crosstalk may provide novel druggable targets to counter vasodegenerative and vasoproliferative eye disease. Here we briefly highlight new evidence suggesting that CNS neurons and guidance cues secreted by neurons such as retinal ganglion cells (RGCs) and photoreceptors have an inherent ability to influence vascular and immune responses in retinopathies. Photoreceptors were likely the first neurons suggested to influence the progression of pathological retinal neovascularization. For instance, a negative correlation was drawn between incidences of retinitis pigmentosa, which causes photoreceptor degeneration, and proliferative DR [7]. Further investigation demonstrated that retinal neovascularization associated with long-standing diabetes mellitus spontaneously regressed with the onset of retinitis pigmentosa [8]. This observation held true in animal models where mice with genetically ablated photoreceptors failed to mount reactive retinal neovascularization in a model of oxygen-induced retinopathy (OIR), which mimics the vasodegenerative phase of ROP and loosely represents the vasoproliferative phases of ROP and DR [8]. These studies draw a link between neuronal energy demand and retinal neovascularization. A mechanism via which central neurons communicate with their environment is through production of classical neuronal guidance cues such as semaphorins, netrins, and ephrins. These proteins are now widely regarded to have angiogenic and inflammatory functions, underscoring their pleiotropic nature. While these signaling proteins were initially thought to exclusively pattern the nervous system, it is now clear they also play a critical role in blood vessel development and influence the immune response during embryogenesis, and tissue …