Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

Fabiola Biasella; Tobias Strunz; Christina Kiel; On Behalf Of The International Amd Genomics Consortium Iamdgc; Bernhard H F Weber; Ulrike Friedrich

doi:10.3390/cells11111766

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

Cells. 2022 May 27;11(11):1766. doi: 10.3390/cells11111766.

Authors

Fabiola Biasella¹, Tobias Strunz¹, Christina Kiel¹, On Behalf Of The International Amd Genomics Consortium Iamdgc², Bernhard H F Weber^{1

3}, Ulrike Friedrich¹

Affiliations

¹ Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
² John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.
³ Institute of Clinical Human Genetics, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

Abstract

The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD.

Keywords: AMD; PAI-1; SERPINE1; VTN; age-related macular degeneration; neovascularization; rs704; vitronectin.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aged
Angiogenesis Inhibitors
Endothelial Cells
Genome-Wide Association Study
Humans
Macular Degeneration* / genetics
Macular Degeneration* / pathology
Middle Aged
Plasminogen Activator Inhibitor 1* / genetics
Vascular Endothelial Growth Factor A
Visual Acuity
Vitronectin* / genetics

Substances

Angiogenesis Inhibitors
Plasminogen Activator Inhibitor 1
SERPINE1 protein, human
Vascular Endothelial Growth Factor A
Vitronectin

Grants and funding

This work was supported in part by a grant from the Pro Retina Foundation, Aachen, Germany for FB. The FV3000 confocal microscope was funded by a grant (INST 89/506-1 FUGG, 91b GG) from the Deutsche Forschungsgemeinschaft (DFG). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.