Concurrent Physiological and Pathological Angiogenesis in Retinopathy of Prematurity and Emerging Therapies

Abstract

Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.

Keywords: Scg3; VEGF; anti-angiogenic therapy; oxygen-induced retinopathy; pathological angiogenesis; physiological angiogenesis; retinopathy of prematurity; secretogranin III; vascular endothelial growth factor.

Figure 1

Fundus image of retinopathy of prematurity (ROP): (A) Healthy retina and (B) ROP retina with tortuous arteries and dilated veins as plus disease.

Figure 2

Retinal structure and vascular systems: (A) Eye structure and (B) Retinal structure and vascular systems. The retina is supplied by two vascular systems: retinal and choroidal vasculatures. The retinal vasculature comprises three layers, including the superficial, intermediate and deep plexuses that are interconnected and supply the upper half of the retina. The bottom half of the retina is avascular, relying on the diffusion from the retinal and choroidal vessels.

Figure 3

(A) Two phases of human ROP and (B) Healthy and OIR flat-mount mouse retina stained with Alexa Fluor 488-conjugated isolectin B4. Scale bar = 500 (top row) and 100 μm (bottom row). Arrowheads indicate pathological retinal neovascularization and neovascular tufts.

Figure 4

Animal OIR models: (A) Mouse model of OIR; (B) Rat OIR model and (C) Dog model of OIR. There is no consensus on an optimal feline OIR model.

Figure 5

Concurrent physiological and pathological angiogenesis in ROP: (A) Physiological angiogenesis in the healthy retina and (B) Concurrent physiological and pathological angiogenesis in the ROP retina. Scg3 receptor is upregulated on pathological neovessels with minimal induction of Scg3 ligand itself, as in contrast to induction of VEGF ligand in ROP.