Choroidal Neovascularization (CNV) describes a destructive process where new, abnormal blood vessels grow from the choroid, the vascular layer beneath the retina, into the space beneath the eye’s light-sensing cells. This pathological development interferes with the function of the macula, the central part of the retina responsible for sharp, detailed vision. The growth of this abnormal vascular network defines the advanced, “wet” form of Age-Related Macular Degeneration (AMD), a leading cause of permanent vision impairment worldwide. Understanding the events that initiate and sustain CNV formation is important for comprehending the mechanisms of vision loss associated with this disease.
Precursors to Neovascular Initiation
The process of CNV begins with age-related changes that compromise the structural and metabolic health of the outer retina. A foundational event involves the dysfunction of the Retinal Pigment Epithelium (RPE), a single layer of cells situated between the retina and the underlying choroid. The RPE is responsible for managing waste products and supplying nutrients to the photoreceptor cells.
As the RPE struggles with aging and metabolic duties, extracellular deposits known as drusen accumulate beneath the RPE cells. These deposits, composed of various waste materials, create a physical and chemical barrier on Bruch’s membrane. Bruch’s membrane is a thin layer that acts as a selective filter between the RPE and the choriocapillaris, the choroid’s dense capillary network.
The presence of drusen and RPE stress causes Bruch’s membrane to thicken and calcify, hindering the exchange of oxygen and nutrients between the choriocapillaris and the RPE. This compromised barrier function creates an environment prone to damage. Persistent inflammation and stress also lead to thinning or loss of the choriocapillaris, reducing the blood supply to the RPE layer. This reduction in vascular support creates localized oxygen deprivation, setting the stage for CNV.
The Molecular Signal Driving Angiogenesis
The lack of oxygen delivery to the RPE and outer retina, known as hypoxia, is the primary trigger for new vessel growth. Cells respond to this oxygen deficit by stabilizing the transcription factor Hypoxia-Inducible Factor 1-alpha (HIF-1α). The stabilization of HIF-1α initiates a cellular response aimed at restoring oxygen supply by stimulating the growth of new blood vessels.
The most potent molecule upregulated by HIF-1α is Vascular Endothelial Growth Factor (VEGF). VEGF is a signaling protein that acts as the main messenger for angiogenesis, promoting the proliferation and migration of vascular cells. Under hypoxic stress, RPE cells begin to secrete large amounts of VEGF toward the choroid.
This overproduction of VEGF disrupts the balance between pro-angiogenic factors (encouraging vessel growth) and anti-angiogenic factors (suppressing it). While these factors maintain vascular stability in a healthy eye, the surge in VEGF overwhelms inhibitory signals. This creates a strong chemical gradient that attracts the endothelial cells of the choroidal vessels, signaling them to breach the protective layers and invade the retinal space.
Physical Invasion and Vessel Maturation
Once choroidal capillary endothelial cells receive the powerful pro-growth signal from VEGF, they activate. This activation causes the endothelial cells to degrade their surrounding basement membrane and adjacent connective tissue. The cells then migrate and proliferate, moving toward the high concentration of VEGF in the sub-RPE space.
The migrating endothelial cells must first breach the compromised Bruch’s membrane, utilizing enzymes to break down the barrier separating the choroid from the RPE. Once past this boundary, the cells multiply and form new vascular tubes, establishing a neovascular complex or membrane. This network is classified by location: remaining beneath the RPE (Type 1 CNV) or growing into the space between the RPE and the neurosensory retina (Type 2 CNV).
These newly formed vessels are structurally flawed and immature, lacking the tight junctions and pericyte coverage that stabilize healthy capillaries. This structural fragility makes the vessel walls highly permeable and leaky. The vessels are often disorganized and highly branched, reflecting their rapid, pathological growth. This lack of proper structure ensures the neovascular complex is functionally unstable and predisposed to leakage and hemorrhage.
Pathological Outcomes of CNV Formation
The immediate consequence of the structurally unsound neovascular complex is the leakage of fluid and blood into the outer retinal layers. The permeable walls of the new vessels allow plasma, proteins, and lipids to exude into the surrounding tissue, a process known as exudation. This accumulation of fluid beneath or within the retina causes the tissue to swell, termed retinal edema.
When this fluid accumulation occurs in the macula, it distorts the light-sensing cells, leading to immediate vision changes such as wavy lines or blurred central sight. The fragile vessels can also rupture easily, resulting in subretinal hemorrhage (bleeding), which damages the retinal architecture. The presence of blood and fluid directly interferes with photoreceptor function, leading to rapid vision loss.
Over time, this continuous process of inflammation, bleeding, and fluid leakage triggers a final, irreversible stage: subretinal scarring, or fibrosis. In this stage, the neovascular complex is replaced by dense, fibrous scar tissue composed primarily of collagen. The scar tissue mechanically destroys the overlaying photoreceptors and RPE cells, permanently obliterating the functional retinal tissue. This fibrovascular scarring is the end-stage outcome of uncontrolled CNV and the cause of severe, permanent central vision impairment.