Khorana Alok A, Sahni Abha, Altland Owen D, Francis Charles W
James P. Wilmot Cancer Center and Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY14642, USA.
Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2110-5. doi: 10.1161/01.ATV.0000090671.56682.D7. Epub 2003 Aug 14.
Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in Mr on selected endothelial cell properties.
Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in Mr. Cell proliferation was assessed by [3H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94+/-2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58+/-8%) or 3-kDa LMWH (60+/-9%, P=0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three- and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58+/-15% and 67+/-9% (P<0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant.
Heparin inhibition of endothelial cell proliferation and organization requires a chain length of >8 saccharide units, with maximal inhibition at Mr of 6 kDa. This Mr dependence differs from that required for anticoagulant activity.
研究表明，接受低分子量肝素（LMWH）治疗的癌症患者生存率有所提高。肿瘤依赖于不断扩张的脉管系统，而肝素可能会影响血管的生长和功能。我们研究了不同分子量的肝素对选定的内皮细胞特性的影响。
将人脐静脉内皮细胞与成纤维细胞生长因子-2及不同分子量的肝素一起培养。通过[3H]胸腺嘧啶核苷掺入法评估细胞增殖，并通过体外试验评估血管形成。6 kDa的低分子量肝素对细胞增殖的抑制作用最大，为94±2%，大于未分级肝素（58±8%）或3 kDa低分子量肝素（60±9%，两者P均=0.02）。肝素四糖、八糖或五糖（磺达肝癸钠）未观察到对增殖的抑制作用。3 kDa和6 kDa的组分分别将基质胶中内皮管的形成减少至成纤维细胞生长因子-2诱导形成的内皮管的58±15%和67±9%（P<0.05），而未分级肝素、四糖、五糖或八糖未观察到抑制作用。6 kDa的低分子量肝素也抑制胎盘外植体中的血管形成。
肝素对内皮细胞增殖和血管形成的抑制作用需要链长>8个糖单位，在分子量为6 kDa时抑制作用最大。这种分子量依赖性不同于抗凝活性所需的分子量依赖性。
