RT Journal Article
T1 Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells
A1 Lehmann, Guillermo L.
A1 Ginsberg, Michael
A1 Nolan, Daniel J.
A1 Rodríguez, Cristina
A1 Martínez González, José
A1 Zeng, Shemin
A1 Voigt, Andrew P.
A1 Mullins, Robert F.
A1 Rafii, Shahin
A1 Rodriguez Boulan, Enrique
A1 Benedicto, Ignacio
AB 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.
PB MDPI
SN 2073-4409
YR 2022
FD 2022-09-24
LK https://hdl.handle.net/20.500.14352/72276
UL https://hdl.handle.net/20.500.14352/72276
LA eng
NO This work was funded by grants EY08538 and GM34107 from NIH, award 2013-028 by the 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 (E.R.-B.). I.B. was supported by the Comunidad Autónoma de Madrid (grants 2017-T1/BMD-5247 and 2021-5A/BMD-20944). The CNIC is supported by the Ministerio de Ciencia e Innovación (MCIN), the Instituto de Salud Carlos III, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MCIN/AEI/10.13039/501100011033). R.F.M. and S.Z. were supported by grant EY024605 from NIH. J.M.-G. was supported by grant RTI2018-094727-B-100 funded by MCIN/AEI/10.13039/501100011033.
NO National Institutes of Health (NIH)
NO Ministerio de Ciencia e Innovación (MCIN)
NO Instituto de Salud Carlos III
NO Fundación Pro-CNIC
NO Tri-Institutional Stem Cell Initiative
NO Research to Prevent Blindness y Dyson Foundations (E.R.-B.)
DS Docta Complutense
RD 23 dic 2025