Product information and disease description Place of product in therapy Disease description

Pathophysiology

12 evidence topics · 7 sources

Retinal structures affected in AMD

“In AMD, important neural, structural, and vascular layers undergo degenerative changes leading to cell death. These include the photoreceptors, which are specialized neurons that convert light into electrical signals that are processed in the visual cortex to form images; the retinal pigment epithelium, a cell layer that is adjacent to the photoreceptors; the Bruch membrane, a collagenous layer that supports and separates the retinal pigment epithelium from the choroid; and the choriocapillaris, which is a fine meshwork of capillaries located in the innermost aspect of the choroid.” (opens the source at this quote in a new tab)

Drusen formation: aging, inflammation, lipid deposition, and oxidative stress

“These aging-related alterations, combined with chronic inflammation, altered lipid and lipoprotein deposition, increased oxidative stress, and impaired extracellular matrix maintenance, lead to extracellular deposits in the neurosensory retina, retinal pigment epithelium, and Bruch membrane” (opens the source at this quote in a new tab)

VEGF-A and VEGFR2 signaling in neovascularization

“Neovascularization is thought to be induced by increased expression of hypoxia-driven vascular endothelial growth factor A (VEGF-A), which is released in response to stimuli such as oxidative stress and complement activation.” (opens the source at this quote in a new tab)
“VEGF promotes angiogenesis by binding to its receptor VEGFR2 and activating downstream pathways that promote endothelial cell proliferation.” (opens the source at this quote in a new tab)

VEGF expression in surgically excised choroidal neovascular membranes

“Surgically removed subfoveal fibrovascular membranes from 18 eyes were analyzed for the expression of VEGF mRNA and protein using in situ hybridization and immunohistochemistry, respectively.” (opens the source at this quote in a new tab)
“Most specimens expressed both VEGF mRNA and protein.” (opens the source at this quote in a new tab)
“Results indicate that VEGF may be of pathogenetic importance for the development of the choroidal neovascularization (age-related macular degeneration)” (opens the source at this quote in a new tab)

“All three choroidal neovascular membranes and all seven epiretinal membranes stained positive for vascular endothelial growth factor.” (opens the source at this quote in a new tab)
“Because expression of some growth factors is stimulated by hypoxia, their localization within choroidal neovascular membranes suggests that hypoxia may be an etiologic factor for choroidal as well as for retinal neovascularization.” (opens the source at this quote in a new tab)

Signaling model: oxidized lipoprotein debris, RPE-derived VEGF, and choroidal endothelial activation

“One predominant component of oxidized lipoprotein debris that accumulates in BrM in neovascular AMD is 7-ketocholesterol, which can induce angiogenesis” (opens the source at this quote in a new tab)
“7-Ketocholesterol is thought to activate microglia to release cytokines, such as TNF, which mediates VEGF expression in RPE cells and its release preferentially from the basal aspects” (opens the source at this quote in a new tab)
“Furthermore, the generated ROS presumably also diminish the RPE barrier integrity and permit secreted VEGF entry into the retina, which promotes choroidal endothelial cell migration, proliferation and eventually MNV formation” (opens the source at this quote in a new tab)

Transition from nonexudative to exudative MNV: PDGF, angiopoietin, and VEGF signaling

“The conversion of non-exudative MNV to exudative MNV is likely to be a major disease transition point in neovascular AMD. Signalling pathways that contribute to this transition may include alterations in MNV pericyte coverage (as potentially regulated by PDGF and TIE2–ANG1 signalling)” (opens the source at this quote in a new tab)
“changes in the local balance of vascular trophic factors (such as VEGF and PEDF)” (opens the source at this quote in a new tab)
“or modulation of complement function” (opens the source at this quote in a new tab)

PDGF-mediated pericyte stabilization and combined VEGF and PDGF receptor inhibition in vitro

“Platelet-derived growth factor (PDGF) signaling is pivotal to pericyte-induced stabilization of choroidal neovascularizations (CNV), and causes partial anti-VEGF resistance.” (opens the source at this quote in a new tab)
“Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro.” (opens the source at this quote in a new tab)

Exudation: leakage, fluid, and breakdown of the blood-retinal barrier

“However, in many eyes, increased intralesional hydrostatic pressure coupled with breakdown of the outer blood–retinal barrier leads to exudation into the subretinal space. Intraretinal fluid accumulation may occur in conjunction with breakdown of the external limiting membrane, or VEGF expression may induce intraretinal leakage independently.” (opens the source at this quote in a new tab)

Fibrosis: wound-healing response and the VEGF to connective tissue growth factor balance

“Fibrosis is a part of the wound-healing response” (opens the source at this quote in a new tab)
“that results from numerous cytokines and factors such as transforming growth factor β1, pigment epithelial growth factor, and connective tissue growth factor.” (opens the source at this quote in a new tab)
“Higher levels of VEGF in relation to connective tissue growth factor may promote vascular growth, whereas decreases in the ratio may lead to increased fibrosis, scarring, and contracture of that tissue.” (opens the source at this quote in a new tab)

Complement dysregulation: CFH Y402H

“The CFH gene product is involved in regulation of the complement system through binding to factor C3b.” (opens the source at this quote in a new tab)
“An alteration of regulation that occurs from modification at the C3b site leads to a defective regulation of the alternative complement pathway and results in an up-regulation of inflammation to host cells that are mediated by the membrane attack complex.” (opens the source at this quote in a new tab)

Causes of vision loss in neovascular AMD: leakage, hemorrhage, fibrosis, and atrophy

“The main causes of vision loss in neovascular AMD include those directly related to the new vessels such as leakage, hemorrhage, and fibrosis. Another important cause of vision loss, particularly in treated cases, is atrophy.” (opens the source at this quote in a new tab)
“In the Age-Related Eye Disease Study 2, 40% of patients demonstrating MNV also showed atrophy at baseline.” (opens the source at this quote in a new tab)

Pericyte recruitment and anti-VEGF resistance in choroidal neovascularization

“While VEGF mainly regulates endothelial cells, PDGF signaling is crucial for cells of the vascular wall, i.e., pericytes and smooth muscle cells” (opens the source at this quote in a new tab)
“Pericytes migrate along a PDGF gradient towards neovessels, proliferate, and associate with the endothelial tubes, leading to vascular stabilization via physical contact, VEGF, and the Ang1/Tie2 system” (opens the source at this quote in a new tab)
“However, PDGF-recruited pericytes are known to support endothelial cells with paracrine VEGF and other pro-survival factors which cannot be complexed as effectively by current anti-VEGF agents” (opens the source at this quote in a new tab)