title: Reduced TIMP-2 in hypoxia enhances angiogenesis.
abstract: Hypoxia, which characterizes ischemia, trauma, inflammation, and solid tumors, recruits monocytes, immobilizes them, and alters their function, leading to an anti-inflammatory and proangiogenic phenotype. Monocyte extravasation from the circulation and their migration in tissues are partially mediated by the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The mechanisms evoked by hypoxia that regulate monocyte migration and activation are not entirely clear. Specifically, the effect of hypoxia on TIMPs in these cells has hardly been investigated. We show that hypoxia reduces TIMP-2 secretion from human primary monocytes and from the monocyte-like cell lines U937 and THP-1 by three- to fourfold (P < 0.01), by inhibiting TIMP-2 transcription through mechanisms that involve the transcription factor SP-1. Hypoxia also lowers TIMP-2 protein secretion from human endothelial cells (by 2-fold, P < 0.05). TIMP-2 levels do not influence the reduced migration of THP-1 cells in hypoxia; however, low TIMP-2 levels enhance endothelial cell migration/proliferation, their ability to form tubelike structures in vitro, and the appearance of mature blood vessels in a Matrigel plug assay in vivo. Thus we conclude that reduced TIMP-2 levels secreted from both hypoxic monocytes and endothelial cells are proangiogenic.
authors.affiliation: Immunology Research Unit, Carmel Medical Ctr., 7 Michal St., Haifa 34362, Israel. rahat_miki@clalit.org.il
authors.forename: Nitza
authors.initials: N
authors.lastname: Lahat
authors.forename: Haim
authors.initials: H
authors.lastname: Bitterman
authors.forename: Miri
authors.initials: M
authors.lastname: Engelmayer-Goren
authors.forename: Doron
authors.initials: D
authors.lastname: Rosenzweig
authors.forename: Lea
authors.initials: L
authors.lastname: Weiss-Cerem
authors.forename: Michal A
authors.initials: MA
authors.lastname: Rahat
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016329:Sp1 Transcription Factor; D019716:Tissue Inhibitor of Metalloproteinase-2