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Choroidal neovascularization (CNV) : clinical and experimental aspects

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posted on 2024-09-03, 05:12 authored by Lennart Berglin

This work comprises different aspects of choroidal neovacularization (CNV); a leading cause of visual loss in the aged. It is an example of angiogenesis and a complication of age-related macular degeneration (AMD) The purpose was to study if patient age influences outcome of CNV surgery, to characterize the cellular content of CNV, to analyze the expression of vascular endothelial growth factor (VEGF) and various matrix metalloproteinases (MMP) and their inhibitors (TIMP) in CNV and to study if MMP-2 influences experimental CNV growth. A national case-control study was designed to retrieve the hospital records for all individuals surgically excised for CNV in Sweden between 1992 and 1999. The results indicated a better visual outcome in younger non-AMD patients with marked visual improvement in 29 % compared to none in patients aged 50 or more. This suggests the need for alternative therapy in AMD patients.

The next three studies analysed archival paraffin-embedded specimens of CNV from AMD patients. An immunohistochemical study using monoclonal antibodies indicated a neovascular core of endothelial cells and pericytes surrounded by a fibrous stroma, extracellular matrix (ECM), maturing towards the periphery enveloped by retinal pigment epithelium (RPE) and remnants of Bruch´s membrane. A wound healing response was suggested by myfibroblasts and an inflammatory nature by macrophages and lymphocytes.

Two additional studies used immunohistochemistry for protein and in-situ hybridization for mRNA analysis. One study featured VEGF expression in vascularized areas with an inflammatory response (fibroblast like cells and endothelial like cells) indicating local neovascular inflammatory zones including activated macrophages. In the other study MMP-2 was localized mainly to the vascular endothelial cell core balanced by different TIMP indicating growth of immature vessels. MMP-9 was expressed in cells at the margin of the membrane often close to a thickened Bruch's membranelike structure under RPE cells. TIMP-3 mRNA was strongly expressed in the RPE layer. The co-localization of MMP-9 ("barrier"-like appearance), TIMP3 and RPE enveloping the CNV could indicate a balancing function.

Finally in an experimental CNV study on mice using immunohistochemistry and in-situ hybridization MMP-2 expression peaked at day 5 with a gradual decline. MMP-2 mRNA expression appeared to be highest at the margins of the membrane which could indicate a front-line of vascular growth. The CNV lesions of MMP-2 deficient mice showed a reduced relative thickness by 31 % as compared to wild type mice using digitized image analysis further indicating that MMP-2 is involved in the formation of experimental CNV in the mouse. Pharmacologic targeting of MMPs may possibly reduce CNV formation in AMD probably combined with other therapies.

List of scientific papers

I. Berglin L, Algvere P, Olivestedt G, Crafoord S, Stenkula S, Hansson LJ, Tomic Z, Kvanta A, Seregard S (2001). The Swedish national survey of surgical excision for submacular choroidal neovascularization (CNV). Acta Ophthalmol Scand. 79(6): 580-4.
https://pubmed.ncbi.nlm.nih.gov/11782223

II. Seregard S, Algvere PV, Berglin L (1994). Immunohistochemical characterization of surgically removed subfoveal fibrovascular membranes. Graefes Arch Clin Exp Ophthalmol. 232(6): 325-9.
https://pubmed.ncbi.nlm.nih.gov/8082839

III. Kvanta A, Algvere PV, Berglin L, Seregard S (1996). Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 37(9): 1929-34.
https://pubmed.ncbi.nlm.nih.gov/8759365

IV. Steen B, Sejersen S, Berglin L, Seregard S, Kvanta A (1998). Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 39(11): 2194-200.
https://pubmed.ncbi.nlm.nih.gov/9761302

V. Berglin L, Sarman S, van der Ploeg I, Steen B, Ming Y, Itohara S, Seregard S, Kvanta A (2002). Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2 deficient mice. [Submitted]

History

Defence date

2002-09-06

Department

  • Department of Clinical Neuroscience

Publication year

2002

Thesis type

  • Doctoral thesis

ISBN-10

91-7349-284-1

Number of supporting papers

5

Language

  • eng

Original publication date

2002-08-16

Author name in thesis

Berglin, Lennart

Original department name

Department of Clinical Neuroscience

Place of publication

Stockholm

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