Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study

• Type of Material: Article
• Authors: Abbas Shirinifard, Indiana University; James Alexander Glazier, Indiana University; Maciej Swat, Indiana University; J. Scott Gens, Indiana University; Fereydoon Family, Emory University; Yi Jiang, Georgia State University; Hans Grossniklaus, Emory University
• Language: English
• Date: 2012-05-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Shirinifard et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pcbi.1002440
• Title of Journal or Parent Work: PLoS Computational Biology
• ISSN: 1553-734X
• Volume: 8
• Issue: 5
• Start Page: e1002440
• End Page: e1002440
• Grant/Funding Information: We have received support from the College of Arts and Sciences, the Office of the Vice President for Research under their Faculty Research Support Program, Research Technologies for computational cycles on the Quarry cluster, and the Biocomplexity Institute, all at Indiana University, Bloomington.; This work was sponsored by National Institutes of Health/National Institute of General Medical Sciences grants 5R01 GM076692-01 and 1R01 GM077138-01A1 and Environmental Protection Agency/National Center for Environmental Research grant R834289 and the National Science Foundation under Grant No. CNS-0521433.; We have received support from Emory College of Arts and Sciences and Departmental Core Grant P30EY06360, Emory University. Jiang Y. is supported by DOE under contract W-7405-ENG-36.
• Keywords: Oxygen; THEORETICAL ESTIMATION; Biophysical simulations; Retina; Science & Technology; Inflammation; BRUCHS MEMBRANE; RETICULAR PSEUDODRUSEN; Angiogenesis; RETINAL-PIGMENT EPITHELIUM; Photoreceptors; Endothelial cells; TUMOR-INDUCED ANGIOGENESIS; Mathematical & Computational Biology; AGE-RELATED MACULOPATHY; MACULAR DEGENERATION; Biochemical Research Methods; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; ENDOTHELIAL GROWTH-FACTOR; SUBRETINAL DRUSENOID DEPOSITS; Basement membrane
• Research Categories: Biology, Bioinformatics; Health Sciences, Opthamology; Biophysics, Medical

Abstract

Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch's membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression.