Immunology Research Unit, Carmel Medical Ctr., 7 Michal St., Haifa 34362, Israel.
Am J Physiol Cell Physiol. 2011 Mar;300(3):C557-66. doi: 10.1152/ajpcell.00177.2010. Epub 2010 Dec 9.
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.
缺氧是缺血、创伤、炎症和实体瘤的特征，它招募单核细胞，使其固定，并改变其功能，导致抗炎和促血管生成表型。单核细胞从循环中渗出并在组织中迁移部分由基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）之间的平衡介导。缺氧调节单核细胞迁移和激活的机制尚不完全清楚。具体来说，缺氧对这些细胞中 TIMP 的影响几乎没有被研究过。我们发现，缺氧通过抑制涉及转录因子 SP-1 的机制，将人原代单核细胞和单核样细胞系 U937 和 THP-1 中的 TIMP-2 分泌减少三到四倍（P < 0.01）。缺氧还降低人内皮细胞（降低 2 倍，P < 0.05）中 TIMP-2 的蛋白分泌。TIMP-2 水平并不影响 THP-1 细胞在缺氧条件下的迁移减少；然而，低水平的 TIMP-2 增强了内皮细胞的迁移/增殖能力，它们在体外形成管状结构的能力，以及在体内 Matrigel 塞实验中成熟血管的出现。因此，我们得出结论，缺氧诱导的单核细胞和内皮细胞分泌的 TIMP-2 水平降低具有促血管生成作用。
