Choroidal Neovascularization: Mechanisms of Endothelial Dysfunction

Abstract

Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.

Keywords: age-related macular degeneration; choroidal neovascularization; disease models; endothelial; vascular mechanisms.

Figure 1

Vascular contribution to wet age-related macular degeneration (AMD) pathogenesis. Top image: Healthy macula; Bottom left image: Vascular changes could occur early in disease progression, manifested as a reduction in choriocapillaris density through loss of endothelial cells; Bottom right image: Vasculopathy is also observed in polypoidal choroidal vasculopathy and typical choroidal neovascularization, such as polypoidal/aneurysmal dilations of vessels and arteriosclerotic features. Mechanisms in common vessel wall pathology in polypoidal choroidal vasculopathy (PCV) include impaired extracellular matrix production and choroidal vascular hyperpermeability.

Figure 2

Vascular mechanisms in choroidal neovascularization.

Figure 3

Sources of recruited endothelial cells in choroidal neovascularization. Endothelial colony-forming cells (yellow) from the bone marrow can be mobilized from the bone marrow into the circulation, migrate to the site of neovascularization, and differentiate into vascular cells that form the new vasculature. Hematopoietic stem cells (blue) can be mobilized to the site of injury, differentiate into endothelial cells and be incorporated into newly formed vasculature. Tissue-resident endothelial side population cells (green) residing in choroidal endothelium have been proposed to contribute to choroidal neovascularization upon injury.