Heparanase as mediator of angiogenesis: mode of action
Heparanase as mediator of angiogenesis: mode of action
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DOI：
10.1096/fj.00-0895fje
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发表时间：
2001-05-29
期刊：
影响因子：
4.8
通讯作者：
Vlodavsky, I
中科院分区：
文献类型：
--
作者：
Elkin, M;Ilan, N;Vlodavsky, I
细胞外基质（ECM）和基底膜（BMs）在血管生成的早期阶段内皮细胞（EC）发芽过程中存在物理屏障，需要酶降解。这些多分子结构也作为肝素结合血管生成因子的储存库。硫酸肝素蛋白聚糖（HSPGs）负责ECM和BM结构的自组装和完整性，以及生长和分化因子的隔离。最近，我们报道了一种降解硫酸肝素（HS）的内切β - d -葡萄糖醛酸酶heparanase的克隆，并为其在肿瘤转移中的作用提供了直接证据。我们现在证明肝素酶与血管生成密切相关，并阐明其作用模式。除了直接参与ECM降解和EC迁移（血管发芽）外，肝素酶还从内皮下ECM释放活性碱性成纤维细胞生长因子（bFGF），并从EC表面释放bFGF刺激HS降解片段。有趣的是，ecm衍生的HS片段很少或没有诱导bFGF促进生长活性的增强。肝素酶的血管生成作用在体内（通过Matrigel plug试验）得到证实，在稳定转染肝素酶基因后，小鼠t淋巴瘤细胞诱导的新生血管形成增加了三到四倍。在小鼠伤口愈合模型中，局部给药重组肝素酶也能增加组织血管。人结肠癌组织的免疫组化染色显示，肝素酶蛋白在新生毛细血管和小血管的内皮中高表达，而在成熟的静止血管中不表达。肝素酶促进肿瘤血管生成和参与肿瘤转移的能力使其成为肿瘤治疗的一个有希望的靶点。
Extracellular matrix (ECM) and basement membranes (BMs) present a physical barrier that requires enzymatic degradation during endothelial cell (EC) sprouting at early stages of angiogenesis. These multimolecular structures also serve as a storage depot for heparin-binding angiogenic factors. Heparan sulfate proteoglycans (HSPGs) are responsible for the self-assembly and integrity of the ECM and BM structure, as well as for sequestration of growth and differentiation factors. Recently, we reported the cloning of heparanase, an endo-beta-D-glucuronidase degrading heparan sulfate (HS), and provided direct evidence for its role in tumor metastasis. We now demonstrate that heparanase is intimately involved in angiogenesis and elucidate its mode of action. Apart from its direct involvement in ECM degradation and EC migration (vascular sprouting), heparanase releases active basic fibroblast growth factor (bFGF) from the subendothelial ECM, as well as bFGF-stimulating HS degradation fragments from the EC surface. Interestingly, ECM-derived HS fragments induced little or no potentiation of the growth-promoting activity of bFGF. The angiogenic effect of heparanase was demonstrated in vivo (via the Matrigel plug assay) by showing a three- to fourfold increase in neovascularization induced by murine T-lymphoma cells after stable transfection with the heparanase gene. Increased tissue vascularity was also observed in a mouse wound-healing model in response to topical administration of recombinant heparanase. Immunohistochemical staining of human colon carcinoma tissue revealed a high expression of the heparanase protein in the endothelium of sprouting capillaries and small vessels, but not of mature quiescent blood vessels. The ability of heparanase to promote tumor angiogenesis and its involvement in tumor metastasis make it a promising target for cancer therapy.