Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
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DOI：
10.1074/jbc.m908930199
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发表时间：
2000-08-11
影响因子：
4.8
通讯作者：
Claesson-Welsh, L
中科院分区：
文献类型：
--
作者：
Lundin, L;Larsson, H;Claesson-Welsh, L
成纤维细胞生长因子(FGFs)可诱导新生血管的形成、血管生成。我们发现选择性去硫化肝素可以调节成纤维细胞生长因子诱导的血管生成。利用缺乏硫酸肝素生物合成的中国仓鼠卵巢细胞(CHO677)，研究了肝素/硫酸肝素在成纤维细胞生长因子受体-1(FGFR-1)信号转导和生物学反应中的作用。在成纤维细胞生长因子-2的存在下，FGFR-1激酶和随后的丝裂原活化蛋白激酶ERK2的活性以剂量依赖的方式增强，而高浓度的肝素则导致活性降低。肝素低聚体的长度(至少8/10聚体)对增强FGFR-1激酶活性至关重要，肝素的N-和2-O-硫酸盐基团是与FGF-2结合所必需的，而FGF-2刺激FGFR-1和ERK2激酶也需要6-O-硫酸盐基团的存在。此外，2-O-和6-O-位的硫酸化是肝素与FGFR-1胞外区160-177个氨基酸对应的富含赖氨酸的多肽结合的先决条件，选择性的6-O-脱硫肝素与成纤维细胞生长因子-2结合但不结合受体，抑制了成纤维细胞生长因子-2诱导的CHO677细胞的增殖，可能是通过取代完整的肝素，此外，6-O-脱硫肝素抑制了成纤维细胞生长因子-2诱导的鸡胚胎血管生成，从而形成了成纤维细胞生长因子-2、肝素、而FGFR-1似乎在FGFR-1的激活和下游信号转导中起关键作用。通过改进的肝素制剂防止复合体的形成可能允许调节成纤维细胞生长因子-2的功能，例如诱导血管生成。
Fibroblast growth factors (FGFs) are known to induce formation of new blood vessels, angiogenesis. We show that FGF-induced angiogenesis can be modulated using selectively desulfated heparin, Chinese hamster ovary cells (CHO677) deficient in heparan sulfate biosynthesis were employed to assess the function of heparin/heparan sulfate in FGF receptor-1 (FGFR-1) signal transduction and biological responses. In the presence of FGF-2, FGFR-1 kinase and subsequent mitogen-activated protein kinase Erk2 activities were augmented in a dose-dependent manner, whereas high concentrations of heparin resulted in decreased activity. The length of the heparin oligomer, minimally an 8/10-mer, was critical for the ability to enhance FGFR-1 kinase activity, The N- and 2-O-sulfate groups of heparin were essential for binding to FGF-2, whereas stimulation of FGFR-1 and Erk2 kinases by FGF-2 also required the presence of 6-O-sulfate groups. Sulfation at 2-O- and 6-O-positions was moreover a prerequisite for binding of heparin to a lysine-rich peptide corresponding to amino acids 160-177 in the extracellular domain of FGFR-1, Selectively 6-O-desulfated heparin, which binds to FGF-2 but fails to bind the receptor, decreased FGF-2-induced proliferation of CHO677 cells, presumably by displacing intact heparin, Furthermore, FGF-2-induced angiogenesis in chick embryos was inhibited by 6-O-desulfated heparin, Thus, formation of a ternary complex of FGF-2, heparin, and FGFR-1 appears critical for the activation of FGFR-1 kinase and downstream signal transduction. Preventing complex formation by modified heparin preparations may allow regulation of FGF-2 functions, such as induction of angiogenesis.