Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye

Abstract

The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization.

Keywords: age-related macular degeneration (AMD); angiogenesis; diabetic retinopathy; immune regulation; neovascularization; vascular endothelial growth factor (VEGF).

Figure1. Anti-VEGF treatment of neovascular eye diseases

Fluorescein angiogram of a control eye (a), a patient with wet AMD (b) or proliferative diabetic retinopathy (PDR) (c). Bright hyperfluorescence demonstrates leakage of dye from the choroidal neovascularization (CNV) under the macula (b, arrow) and retinal neovascularization (c, arrows). Anomalous circulation characterized by neovascularization, ischemia and collateral vessel formation can be noted in the retina of PDR patient (c). Optical coherence tomography (OCT) of the central retina of an AMD patient before (d) and after (e) anti-VEGF treatments. Intraocular injections of anti-VEGF neutralizing antibody (e) led to resolution of cystoid macular edema (d, stars) and significant improvement in the CNV (d, arrowheads). OCT of neovascular AMD patient (f) shows a pigment epithelial detachment (PED) overlying the CNV (f, arrow). After intravitreal anti-VEGF treatment (g), there is an increase in the size of the PED (including the CNV complex) as well as the amount of subretinal fluid indicating persistent CNV activity (g, arrows).

Figure2. Role of VEGF in retinal angiogenesis and homeostasis

Schematic cross-section through the human eye (a) and detailed representation of the retina (b). In the retina, VEGF is produced and secreted by neurons, glia and vascular endothelial cells. Additionally, different cell types also express VEGF receptor. During retinal vascular development, VEGF signaling plays an essential role in the formation and patterning of the vascular network (vascular plexus). The retinal pigmented epithelium (RPE)-derived VEGF is responsible for the development and the maintenance of the choriocapillaries. It also provides neurotrophic support to photoreceptors, retinal bipolar cells (RBC) and retinal ganglion cells (RGC). Retinal VEGF expression is upregulated in response to hypoxia and contributes to pathologic neovascularization. In these conditions, the majority of the VEGF is produced by Müller glial cells and astrocytes.

Figure3. Immune regulation of VEGF-independent angiogenesis

Depending on their activation state, macrophages/microglia can differentially modulate endothelial cell growth. M1 macrophages are anti-angiogenic, whereas M2 macrophages promote angiogenesis. The effect of macrophages on endothelial cells can be contact-dependent or through secretion of angiogenic factors. Complement factor B (cfB), a component of the alternative complement pathway, in combination with the complement inhibitor (CD55), selectively inhibits pathological neovessel formation. In hypoxic conditions, CD55 is downregulated in endothelial cells therefore allowing the specific targeting of neovessels by cfB. Complement components can also modulate macrophage activation. Complement components C3 and C5 polarize macrophages to an M1 anti-angiogenic phenotype. Activation of microglial cells upon exposure to ischemia induces the secretion of IL-1β and subsequent production of Semaphorin-3a (Sema-3A) by retinal neurons. Sema-3A induces degeneration of the retinal vasculature. The adaptive immunity may promote angiogenesis through autoantibodies or secretion of IL-17 by T cells. Ocular angiogenesis can be further regulated through the remodeling of the extracellular matrix (ECM). Activation of ECM-stimulated pathways through neuropilin-1 (NRP1) signaling also promotes angiogenesis in the eye.