Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin.

K Norrby, P Ostergaard
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引用次数: 60

Abstract

We recently reported that the subcutaneous (s.c.) administration of a low-molecular-weight heparin (LMWH) fraction significantly inhibited de novo angiogenesis in the mesentery induced by the intraperitoneal (i.p.) injection of saline to adult rats compared with unfractionated heparin and high-molecular-weight heparin (HMWH) fractions. The present study assesses the effect on basic fibroblast growth factor (bFGF)-mediated de novo angiogenesis in the mesentery of the systemic administration of a LMWH fraction (2.6 kD) and a series of four HMWH fractions (about 20 kD) with varying degrees of polydispersity, charge density and anticoagulant activity. bFGF, a prototypic heparin-binding angiogenic growth factor, was injected i.p. at 220 pM on days 0-4. The heparins were given s.c. on days 0-13 or 0-14 at doses which were approximately within the range used clinically. Angiogenesis was assessed by microscopic morphometry and image analysis in groups of animals killed on days 14 and 15. Compared with the saline control, the LMWH and three of the HMWHs significantly inhibited angiogenesis in terms of microvascular length (MVL), a measure of microvascular density. Interestingly, the vascularized area (VA), a measure of microvascular spatial extension, and the total microvascular length (VA x MVL) were significantly lower in the LMWH-treated animals than in the animals treated with one of the HMWHs. The total microvascular length was, moreover, significantly reduced in the LMWH-treated animals compared with the combined data of all the HMWH-treated animals. No significant effects were related to the degree of charge density and anticoagulant activity of the heparins. In view of the putative significant angiogenic role of bFGF in human angiogenesis diseases, the present findings may have implications for the choice of anticoagulant treatment modality for patients suffering from cancer and other angiogenesis diseases.

低分子量肝素比高分子量肝素更有效地抑制碱性成纤维细胞生长因子介导的新生血管生成。
我们最近报道,与未分离肝素和高分子量肝素(HMWH)相比,皮下注射低分子肝素(LMWH)组分可显著抑制成年大鼠腹腔注射生理盐水诱导的肠系膜新生血管生成。本研究评估了系统给药低分子肝素部分(2.6 kD)和一系列四种低分子肝素部分(约20 kD)对碱性成纤维细胞生长因子(bFGF)介导的肠系膜新生血管生成的影响,这些部分具有不同程度的多分散性、电荷密度和抗凝血活性。bFGF是一种原型肝素结合血管生成生长因子,于第0-4天的220 pM腹腔注射。在0-13或0-14天给予肝素,剂量大致在临床使用范围内。在第14天和第15天处死的各组动物,采用显微形态学和图像分析评估血管新生情况。与生理盐水对照组相比,低分子肝素和三种低分子肝素在微血管长度(微血管密度的量度)方面显著抑制血管生成。有趣的是,低分子whs组动物的血管化面积(VA)(微血管空间延伸的量度)和微血管总长度(VA x MVL)明显低于其中一种低分子whs组动物。此外,与所有hmwh处理动物的综合数据相比,lmwh处理动物的总微血管长度显着减少。肝素的电荷密度和抗凝血活性对其无显著影响。鉴于假定bFGF在人类血管生成疾病中具有重要的血管生成作用,本研究结果可能对癌症和其他血管生成疾病患者的抗凝治疗方式的选择具有启示意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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