{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:06:31Z","timestamp":1785153991563,"version":"3.55.0"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL093339"],"award-info":[{"award-number":["R01HL093339"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG074289"],"award-info":[{"award-number":["R01AG074289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL179583"],"award-info":[{"award-number":["R01HL179583"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteoglycan Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Axon guidance molecules, initially identified for their roles in neural development, are now recognized as crucial regulators of angiogenesis and blood vessel patterning. Among these, Slit3 promotes endothelial cell migration, proliferation, and vascular network formation by signaling through the endothelial\u2010specific receptor Robo4. This interaction depends on heparan sulfate (HS) as a co\u2010receptor for assembly of the Slit3\u2013Robo4 complex, although the specific HS proteoglycan involved has not yet been identified. Our recent work also shows that Robo4 ectodomain shedding by ADAM10 and ADAM17 suppresses this angiogenic pathway. Here, we identify matrix metalloproteinase\u20102 (MMP2) as an additional suppressor of Slit3\u2013Robo4 signaling.\n                    <jats:italic>MMP2<\/jats:italic>\n                    expression correlates with\n                    <jats:italic>Slit3<\/jats:italic>\n                    in diaphragm mesenchymal and lung stromal cells and inhibits Slit3\u2010induced endothelial cell proliferation, migration, and angiogenesis. Furthermore, we identify glypican\u20104 (GPC4) as an HS proteoglycan mediating Slit3\u2013Robo4 co\u2010receptor function and show that MMP2 cleaves GPC4, thereby disrupting Slit3\u2013Robo4 signaling. These findings establish GPC4 as a vital co\u2010receptor for Slit3\u2013Robo4 signaling and reveal MMP2\u2010mediated GPC4 shedding as a novel mechanism to regulate angiogenic responses. This study uncovers an additional level of proteolytic regulation in Slit3\u2013Robo4 signaling\u2010driven angiogenesis, broadening our understanding of how extracellular proteinases influence ligand\u2013receptor\/co\u2010receptor interactions.\n                  <\/jats:p>","DOI":"10.1002\/pgr2.70044","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T03:50:02Z","timestamp":1768967402000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MMP2 Sheds Glypican\u20104 to Suppress Slit3\u2010Robo4 Signaling and Angiogenesis"],"prefix":"10.1002","volume":"4","author":[{"given":"Wenyuan","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R.","family":"Orta","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huquan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-2719","authenticated-orcid":false,"given":"Lianchun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Tampa Florida 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