Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

Abstract

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 ...

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

“…In the retina, Sema3A, E and F were reported as vaso-repulsive cues in developmental retinal angiogenesis (10)(11)(12). In addition, SEMA-3A, C, and E are all involved in pathological retinal neovascularization in eye disease models (13)(14)(15). Both SEMA3A and -E are expressed in the retinal ganglion cells (RGCs) (14).…”

Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A

“…Strikingly, although the hypoxia that accompanies ischemia is a well-known driver of vascular growth, revascularization of ischemic nervous tissue is often inadequate (1,2) in conditions such as stroke and ischemic retinopathies. Therapeutic strategies that allow more rapid revascularization would be of tremendous benefit, reducing ischemia-induced cellular damage and also suppressing the harmful aberrant pathologic neovascularization that can occur.…”

“…Ischemic neurons possess the ability either to promote or resist revascularization. For example, semaphorin 3A (Sema3A) and Sema3E, secreted by ischemic ganglion cells, serve to suppress vascular regrowth into the ischemic zone in a mouse model of ischemic retinopathy (1,2). This suggests a therapeutic avenue consisting of treatments that shift neuronal elements toward a repair response, or alternatively, treatments that target neurovascular interactions, including molecular mediators.…”

Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction

“…In an adult murine demyelination model, Sema3A has been shown to impair oligodendrocyte precursor cell recruitment to the demyelinated area. Ischemic neurons can prevent vascular regeneration of neural tissue by secreting Sema3A (11). Systemic and targeted delivery of Sema3A has been shown to inhibit tumor angiogenesis (12).…”