What is the pathophysiology of choroidal neovascularization (CNV)?

Updated: Jul 27, 2020
  • Author: Lihteh Wu, MD; Chief Editor: Andrew A Dahl, MD, FACS  more...
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Mechanisms of CNV are not well understood. Virtually any pathologic process that involves the RPE and damages the Bruch membrane can be complicated by CNV. CNV may be considered as a wound healing response to an insult of the RPE. A protein derived from the RPE, pigment epithelium derived factor (PEDF), was found to have an inhibitory effect on ocular neovascularization. Another peptide, vascular endothelium growth factor (VEGF), is a well-known ocular angiogenic factor.

The balance between antiangiogenic factors (eg, PEDF) and angiogenic factors (eg, VEGF) is speculated to determine the growth of CNV. The cause of VEGF upregulation in CNV remains unclear. VEGF upregulation is known to occur secondary to hypoxia, high glucose and protein kinase c activation, advanced glycation end products, reactive oxygen species, activated oncogenes, and a variety of cytokines.

VEGF has been temporally and spatially correlated with the development of CNV. Histopathologic specimens obtained from submacular surgery reveal the presence of VEGF in CNV. In addition, several researchers have induced CNV formation in animal models by overexpressing VEGF. Once secreted, VEGF binds to its tyrosine kinase receptors in endothelial cells activating several signal transduction pathways. Activation of VEGF induces vascular permeability, endothelial cell proliferation, and cell migration. The end product is the formation of a network of new vessels. These new vessels were previously thought to occur secondary to angiogenesis.

Angiogenesis can be defined as the growth of new vessels from preexisting vessels. Recent evidence suggests that CNV forms from both angiogenesis and vasculogenesis. [9] Vasculogenesis may be defined as the de novo growth of new blood vessels.

In an experimental model of CNV, it has been estimated that up to 20% of endothelial cells are bone marrow–derived progenitor cells that have been mobilized from the bone marrow. [10] These endothelial progenitor cells join the activated endothelial resident cells and incorporate into the nascent vascular tubular structure. The inhibition of endothelial progenitor cells mobilization from the bone marrow significantly reduced the size of the CNV lesion. [11, 12] Migration of endothelial cells requires remodelling of the extracellular matrix. Integrins and metalloproteinases play an important role at this stage. With time, vascular maturation and stability is achieved. Vascular maturation is intimately associated with platelet-derived growth factor (PDGF)-BB, which recruits pericytes to the new vessels.

As new choroidal blood vessels grow, they may extend into the sub-RPE space (Gass type 1) or into the subretinal space (Gass type 2). The location, growth pattern, and type (1 or 2) of CNV depend on the patient's age and the underlying disease. Bleeding and exudation occur with further growth, accounting for the visual symptoms. Alternatively, abnormal blood vessels may originate from an intraretinal location and grow into the subretinal space. This pattern of growth has been named retinal angiomatous proliferation (RAP), or type 3 neovascularization. [13]

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