Inhibition of angiogenesis on glycated collagen lattices
Inhibition of angiogenesis on glycated collagen lattices
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DOI：
10.1007/s001250050937
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发表时间：
1998-05-01
期刊：
影响因子：
8.2
通讯作者：
Iguchi, A
中科院分区：
文献类型：
--
作者：
Kuzuya, M;Satake, S;Iguchi, A
糖尿病患者细胞外基质蛋白的晚期糖基化终产物（AGE）积累已被证实与糖尿病并发症的严重程度有显著相关性。AGE积累诱导基质蛋白交联形成，导致基质纤维刚度增加，降低基质蛋白对蛋白水解降解的敏感性。我们研究了糖基化诱导的胶原交联是否会影响血管内皮细胞的行为，如侵袭、增殖和分化，使用i型胶原三维基质中毛细血管样结构形成的体外血管生成模型。凝胶中有组织的毛细血管样索状结构。我们发现，在条件培养基中，内皮细胞对糖化胶原凝胶的侵袭明显减弱，但对蛋白酶活性没有任何影响，包括细胞相关的纤溶酶原激活剂和基质金属蛋白酶。此外，糖基化胶原凝胶也抑制了随后的毛细血管样脊髓形成。相比之下，与对照胶原凝胶相比，糖基胶原凝胶（含或不含血管生成因子）增强了内皮细胞的增殖。这些结果表明，通过糖基化诱导的交联形成的细胞外基质蛋白的结构改变影响内皮细胞和细胞外基质之间的相互作用，导致糖尿病患者足够的新生血管受损。
Advanced glycation endproduct (AGE) accumulation in extracellular matrix proteins has been demonstrated in diabetic patients with a significant correlation with the severity of diabetic complications. AGE accumulation induces matrix protein cross-link formation, resulting in an increased stiffness of matrix fibres and the reduction of the susceptibility of matrix proteins to proteolytic degradation. We examined whether glycation-induced collagen cross-linking may affect vascular endothelial cell behaviours such as invasion, proliferation and differentiation, using the in vitro angiogenesis model of capillary-like structure formation in three-dimensional matrices of collagen type I. Endothelial cells cultured on collagen gel with angiogenic factors (the combination of fibroblast growth factor-2 and vascular endothelial growth factor) invaded the underlying collagen matrix, and organized capillary-like cord structures in the gel. We found that endothelial cell invasion into glycated collagen gel was significantly attenuated without any effect on proteinase activity including cell-associated plasminogen activator and matrix metalloproteinase in the conditioned medium. In addition, subsequent capillary-like cord formation was also inhibited in glycated collagen gel. In contrast, endothelial cell proliferation was enhanced on glycated collagen gel with or without angiogenic factors compared with control collagen gel. These results suggest that the structural alterations of extracellular matrix proteins through the glycation-induced cross-link formation affect the interaction between endothelial cell and extracellular matrix, resulting in the impairment of an adequate neovascularization in diabetic patients.