{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:10:11Z","timestamp":1781104211866,"version":"3.54.1"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,11,8]]},"abstract":"<jats:p>\n                    Matrix metalloproteinase-2 (MMP-2) plays an essential role in angiogenesis and arteriogenesis, two processes critical to restoration of tissue perfusion after ischemia.\n                    <jats:italic>MMP-2<\/jats:italic>\n                    expression is increased in tissue ischemia, but the responsible mechanisms remain unknown. We studied the transcriptional activation of the MMP-2 gene in a model of hindlimb ischemia by using various MMP-2-lacZ reporter mice and chromatin immunoprecipitation. MMP-2 activity and mRNA were increased after hindlimb ischemia. Mice with targeted deletion of\n                    <jats:italic>MMP-2<\/jats:italic>\n                    had impaired restoration of perfusion and a high incidence of limb gangrene, indicating that MMP-2 plays a critical role in ischemia-induced revascularization. Ischemia induced the expression and binding of c-Fos, c-Jun, JunB, FosB, and Fra2 to a noncanonical activating protein-1 (AP-1) site present in the\n                    <jats:italic>MMP-2<\/jats:italic>\n                    promoter and decreased binding of the transcriptional repressor JunD. Ischemia also activated the expression and binding of p53 to an adjacent enhancer site (RE-1) and increased expression and binding of nuclear factor of activated T-cells-c2 to consensus sequences within the first intron. Deletion of either the 5\u2032 AP-1\/RE-1 region of the promoter or substitution of the first intron abolished ischemia-induced\n                    <jats:italic>MMP-2<\/jats:italic>\n                    transcription\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Thus, AP-1 transcription factors and intronic activation by nuclear factor of activated T-cells-c2 act in concert to drive ischemia-induced MMP-2 transcription. These findings define a critical role for MMP-2 in ischemia-induced revascularization and identify both previously uncharacterized regulatory elements within the\n                    <jats:italic>MMP-2<\/jats:italic>\n                    gene and the cognate transcription factors required for\n                    <jats:italic>MMP-2<\/jats:italic>\n                    activation\n                    <jats:italic>in vivo<\/jats:italic>\n                    after tissue ischemia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0508085102","type":"journal-article","created":{"date-parts":[[2005,10,28]],"date-time":"2005-10-28T20:39:12Z","timestamp":1130531952000},"page":"16345-16350","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["Intronic regulation of\n                    <i>matrix metalloproteinase-2<\/i>\n                    revealed by\n                    <i>in vivo<\/i>\n                    transcriptional analysis in ischemia"],"prefix":"10.1073","volume":"102","author":[{"given":"Jackie G.","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sia","family":"Dahi","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev","family":"Mahimkar","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel L.","family":"Tulloch","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Alfonso-Jaume","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Lovett","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajabrata","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, San Francisco Veterans Affairs Medical Center, and Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94121; and Division of Nephrology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2005,10,28]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"e120","volume":"20","year":"2000","unstructured":"Tronc, F., Ziad, M., Lehoux, S., Wassef, M., Esposito, B. & Tedgui, A. 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