Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells
Lehmann, Guillermo L. (Regeneron Pharmaceuticals. Inc.)
Ginsberg, Michael (Angiocrine Bioscience. Inc.)
Nolan, Daniel J. (Angiocrine Bioscience. Inc.)
Rodríguez, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Martínez-González, José (Institut d'Investigació Biomèdica Sant Pau)
Zeng, Shemin (Institute for Vision Research. Department of Ophthalmology and Visual Sciences. The University of Iowa)
Voigt, Andrew P. (Institute for Vision Research. Department of Ophthalmology and Visual Sciences. The University of Iowa)
Mullins, Robert F. (Institute for Vision Research. Department of Ophthalmology and Visual Sciences. The University of Iowa)
Rafii, Shahin (Ansary Stem Cell Institute. Department of Medicine. Division of Regenerative Medicine. Weill Cornell Medicine)
Rodriguez-Boulan, Enrique (Margaret Dyson Vision Research Institute. Department of Ophthalmology. Weill Cornell Medicine)
Benedicto, Ignacio (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)

Fecha:	2022
Resumen:	Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch's membrane and visual function.
Ayudas:	Agencia Estatal de Investigación CEX2020-001041-S Ministerio de Ciencia e Innovación RTI2018-094727-B-100
Nota:	Altres ajuts: NIH (EY08538, GM34107, EY024605); Tri-Institutional Stem Cell Initiative established by a grant from The Starr Foundation and by Departmental grants from Research to Prevent Blindness and Dyson Foundations (award 2013-028); Comunidad Autónoma de Madrid (2017-T1/BMD-5247, 2021-5A/BMD-20944); Instituto de Salud Carlos III; Pro-CNIC Foundation.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alpha-2-macroglobulin (A2M) ; Retinal pigment epithelium (RPE) ; Vascular endothelial growth factor-A (VEGF-A) ; Endothelial cells (ECs) ; Extracellular matrix (ECM) ; Matrix metalloproteinase2 (MMP-2) ; Protease inhibitor ; Age-related macular degeneration (AMD) ; Bruch's membrane
Publicado en:	Cells, Vol. 11 Núm. 19 (october 2022) , p. 2975, ISSN 2073-4409

DOI: 10.3390/cells11192975
PMID: 36230937

16 p, 1.4 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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