HYPOXIA-MEDIATED INDUCTION OF ACIDIC/BASIC FIBROBLAST GROWTH-FACTOR AND PLATELET-DERIVED GROWTH-FACTOR IN MONONUCLEAR PHAGOCYTES STIMULATES GROWTH OF HYPOXIC ENDOTHELIAL-CELLS
HYPOXIA-MEDIATED INDUCTION OF ACIDIC/BASIC FIBROBLAST GROWTH-FACTOR AND PLATELET-DERIVED GROWTH-FACTOR IN MONONUCLEAR PHAGOCYTES STIMULATES GROWTH OF HYPOXIC ENDOTHELIAL-CELLS
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DOI：
10.1073/pnas.92.10.4606
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发表时间：
1995-05-09
影响因子：
11.1
通讯作者：
STERN, DM
中科院分区：
文献类型：
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作者：
KUWABARA, K;OGAWA, S;STERN, DM
伤口修复和肿瘤血管化依赖于血管在缺氧组织中的生长。尽管缺氧会减缓内皮细胞（EC）的增殖并抑制EC碱性成纤维细胞生长因子（bFGF）的表达，但我们报道，暴露于PO2约为12-14 torr （1 torr = 133.3 Pa）的巨噬细胞（MPs）以时间依赖性的方式合成和释放血小板衍生生长因子（PDGF）和酸性/碱性FGFs (a/bFGFs)，从而刺激缺氧内皮细胞的生长。低氧mp条件培养基在固定化肝素上以上升的NaCl梯度层析三个有丝分裂活性峰：第一个峰的活性被PDGF抗体中和；第二个峰的活性被aFGF抗体中和；第三峰的活性被bFGF抗体中和，暴露于缺氧环境的MPs代谢标记的解液和上清液显示，在细胞活力未发生变化的情况下，免疫可沉淀的PDGF和a/bFGF的合成和释放增加。暴露于镍或钴的常氧MPs诱导bFGF和PDGF，表明含有血红素的氧传感器可能参与MP对生长因子的加工。尽管叠氮化钠等代谢抑制剂没有作用，但这些结果表明，在缺氧环境中，缺氧刺激MP释放PDGF和a/bFGF，诱导EC增殖并可能促进血管生成，这是一种旁分泌模型。
Wound repair and tumor vascularization depend upon blood vessel growth into hypoxic tissue. Although hypoxia slows endothelial cell (EC) proliferation and suppresses EC basic fibroblast growth factor (bFGF) expression, we report that macrophages (MPs) exposed to PO2 approximate to 12-14 torr (1 torr = 133.3 Pa) synthesize and release in a time-dependent manner platelet-derived growth factor (PDGF) and acidic/basic FGFs (a/bFGFs), which stimulate the growth of hypoxic ECs, Chromatography of hypoxic MP-conditioned medium on immobilized heparin with an ascending NaCl gradient resolved three peaks of mitogenic activity: activity of the first peak was neutralized by antibody to PDGF; activity of the second peak was neutralized by antibody to aFGF; and activity of the third peak was neutralized by antibody to bFGF, Metabolically labeled lysates and supernatants from MPs exposed to hypoxia showed increased synthesis and release of immunoprecipitable PDGF and a/bFGF in the absence of changes in cell viability, Possible involvement of a heme-containing oxygen sensor in MP elaboration of growth factors was suggested by the induction of bFGF and PDGF by normoxic MPs exposed to nickel or cobalt, although metabolic inhibitors such as sodium azide were without effect, These results suggest a paracrine model in which hypoxia stimulates MP release of PDGF and a/bFGF, inducing EC proliferation and potentially promoting angiogenesis in hypoxic environments.