FIBROBLAST GROWTH-FACTORS ARE PRESENT IN THE EXTRACELLULAR-MATRIX PRODUCED BY ENDOTHELIAL-CELLS INVITRO - IMPLICATIONS FOR A ROLE OF HEPARINASE-LIKE ENZYMES IN THE NEOVASCULAR RESPONSE
FIBROBLAST GROWTH-FACTORS ARE PRESENT IN THE EXTRACELLULAR-MATRIX PRODUCED BY ENDOTHELIAL-CELLS INVITRO - IMPLICATIONS FOR A ROLE OF HEPARINASE-LIKE ENZYMES IN THE NEOVASCULAR RESPONSE
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DOI：
10.1016/0006-291x(87)90292-0
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发表时间：
1987-01-30
影响因子：
3.1
通讯作者：
LING, N
中科院分区：
文献类型：
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作者：
BAIRD, A;LING, N
由血管和毛细血管内皮细胞产生的细胞外基质 (ECM) 的盐提取物含有与碱性和酸性成纤维细胞生长因子 (FGF) 无法区分的有丝分裂原。这些提取物中发现的生物活性通过肝素-琼脂糖亲和柱保留，并用与洗脱 FGF 所需的盐浓度相似的盐浓度（即 1.1 - 2M NaCl）进行洗脱。针对碱性和酸性 FGF 合成片段产生的抗血清与 ECM 衍生的有丝分裂原发生交叉反应。放射性碘标记的碱性 FGF 与血管和毛细血管内皮细胞形成的 ECM 结合，这一结果与在 ECM 上发现的 FGF 样有丝分裂原的观察结果一致。当 ECM 用肝素酶或肝素酶预处理时，FGF 与 ECM 的结合可以忽略不计，这表明有丝分裂原与 ECM 中的肝素样糖胺聚糖相互作用。用几种级别的透明质酸酶、软骨素酶或软骨-4-硫酸酯酶或软骨-6-硫酸酯酶消化 ECM 对 125I-FGF 与 ECM 的结合影响很小或没有影响。鉴于许多细胞（如果不是全部）都会产生硫酸乙酰肝素，并且这些糖胺聚糖与细胞的外表面和 ECM 相关，因此提出了一个模型，表明肿瘤和一些正常组织诱导的新生血管反应可能至少部分是由肝素酶样酶的初始释放而不是血管生成因子（FGF）本身介导的。这些酶的释放将有效地动员 ECM 二次局部释放 FGF，然后诱导增殖反应。
Salt extracts of the extracellular matrix (ECM) that is produced by vascular and capillary endothelial cells contain mitogens that are indistinguishable from basic and acidic fibroblast growth factors (FGFs). The biological activity found in these extracts is retained by heparin-Sepharose affinity columns and elutes with salt concentrations similar to those required to elute FGFs (i.e. 1.1 - 2M NaCl). Antisera raised against synthetic fragments of basic and acidic FGF crossreact with the ECM-derived mitogens. Radioiodinated basic FGF binds to the ECM formed by both vascular and capillary endothelial cells, a result that is consistent with the observation that FGF-like mitogens are found on the ECM. The binding of FGF to the ECM is negligible when the ECM has been pretreated with heparinase or heparitinase suggesting that the mitogen is interacting with a heparin-like glycosaminoglycan in the ECM. The digestion of the ECM with several grades of hyaluronidase, chondroitinase or chondro-4-sulfatase or chondro-6-sulfatase has little or no effect on 125I-FGF binding to the ECM. In view of the fact that many, if not all cells, produce heparan sulfates and that these glycosaminoglycans are associated with the external surface of the cell and the ECM, a model is proposed suggesting that the neovascular response induced by tumours and some normal tissues may be mediated at least in part, by the initial release of heparinase-like enzymes rather then angiogenic factors (FGFs) per se. The release of these enzymes would effectively mobilize a secondary local release of FGF from the ECM which then induces a proliferative response.