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Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Vascular endothelial growth factor (VEGF) inhibition is currently the first-line therapy for various retinal vascular disorders, however there is a strong need to develop novel therapies to target other molecules involved in the angiogenic process. In addition to well-known antibiotic properties, Doxycycline (DXC) has versatile non-antibiotic properties, therefore, our goal was to evaluate the effect of DXC on matrix metalloproteinase-2 (MMP-2) as a potential therapeutic alternative for retinal neovascularization (NV), using vascular and glial cells and the oxygen-induced retinopathy (OIR) mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>MGC and BAEC viability under DXC treatment was evaluated using an MTT assay. Changes of Pro MMP-2 and MMP-2 activity were measured by gelatin zymography assay in MIO-M1 cells incubated with DXC under normoxia and hypoxic conditions. VEGF-induced angiogenesis was assessed by tube formation assay in BAEC incubated with DXC for 24 h C57BL\/6 mice exposed to OIR model, were intravitreally injected with a single dose of DXC at post-natal day (P)12 and retinas evaluated at P17.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DXC significantly decreased pro MMP-2 and MMP-2 activity in MIO-M1 supernatants and increased hypoxic-induced mRNA expression of pigmentary epithelium-derived factor (PEDF). Moreover, DXC inhibited the VEGF-induced tube formation in endothelial cells. A single intraocular administration of DXC at postnatal day (P) 12 showed a significant decrease of pro MMP-2 and MMP-2 activity together with a reduced NV and vaso-obliteration in P17 mouse retinas of OIR eyes, while no significant difference was observed neither in MMP-2 nor in VEGF protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our results lead to propose a possible DXC mechanism for inhibition of angiogenesis through the modulation of MMPs involving the VEGF\/PEDF balance. These findings underscore the potential repositioning of DXC as a new possibility for treating ocular proliferative diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1561250","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T07:46:45Z","timestamp":1743407205000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Doxycycline inhibits MMP-2 retinal activity and modulates the angiogenic process in vitro and in vivo"],"prefix":"10.3389","volume":"13","author":[{"given":"Mar\u00eda Lina","family":"Formica","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Constanza","family":"Paz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Victoria","family":"Vaglienti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula Virginia","family":"Subirada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamila","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana Bel\u00e9n","family":"Joray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Domingo","family":"Luna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo Federico","family":"Barcelona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago Daniel","family":"Palma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Cecilia","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.phrs.2015.11.027","article-title":"Targeting VEGF in eye neovascularization: what\u2019s new? a comprehensive review on current therapies and oligonucleotide-based interventions under development","volume":"103","author":"Amadio","year":"2016","journal-title":"Pharmacol. 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