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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\u2019s membrane and visual function.<\/jats:p>","DOI":"10.3390\/cells11192975","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T21:14:28Z","timestamp":1664140468000},"page":"2975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"Guillermo L.","family":"Lehmann","sequence":"first","affiliation":[{"name":"Margaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USA"},{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Angiocrine Bioscience, Inc., San Diego, CA 92121, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-0813","authenticated-orcid":false,"given":"Daniel J.","family":"Nolan","sequence":"additional","affiliation":[{"name":"Angiocrine Bioscience, Inc., San Diego, CA 92121, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-5647","authenticated-orcid":false,"given":"Cristina","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Institut de Recerca Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain"},{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3894-7166","authenticated-orcid":false,"given":"Jos\u00e9","family":"Mart\u00ednez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain"},{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Instituto de Investigaciones Biom\u00e9dicas de Barcelona-Consejo Superior de Investigaciones Cient\u00edficas (IIBB-CSIC), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shemin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Institute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P.","family":"Voigt","sequence":"additional","affiliation":[{"name":"Institute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5006-0891","authenticated-orcid":false,"given":"Robert F.","family":"Mullins","sequence":"additional","affiliation":[{"name":"Institute for Vision Research, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52246, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahin","family":"Rafii","sequence":"additional","affiliation":[{"name":"Ansary Stem Cell Institute, Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Rodriguez-Boulan","sequence":"additional","affiliation":[{"name":"Margaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Benedicto","sequence":"additional","affiliation":[{"name":"Margaret Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USA"},{"name":"Departamento de Inmunolog\u00eda, Oftalmolog\u00eda y ORL, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain"},{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol. 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