Inhibition of angiogenesis through modulation of collagen metabolism.
Inhibition of angiogenesis through modulation of collagen metabolism.
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发表时间：
1988-07
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通讯作者：
D. Ingber;J. Folkman
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作者：
D. Ingber;J. Folkman
血管抑制类固醇和肝素的组合诱导基底膜破裂、毛细血管收缩和内皮细胞变圆，作为其抗血管生成作用的一部分（Ingber DE，Madri JA，Folkman J：Endocrinology 119：1768，1986）。基质代谢的特定调节剂进行了检查，其影响和毛细血管的发展，在不断增长的鸡绒毛尿囊膜探索的可能性，细胞外基质（ECM）的结构改变可能是因果关系参与的抗血管生成机制。脯氨酸类似物（1-氮杂环丁烷-2-羧酸、顺式-羟脯氨酸、d，L-3，4-脱氢脯氨酸、硫代脯氨酸）和脯氨酰羟化酶抑制剂（α，α-联吡啶）可干扰三螺旋形成并防止胶原沉积，从而诱导生长中的毛细血管消退。β-氨基丙腈，胶原交联的抑制剂，也是抗血管生成，虽然抑制剂的糖胺聚糖沉积（β-甲基d-木糖苷）不是。次优剂量的活性胶原调节剂与血管生成抑制类固醇或肝素的组合导致其抗血管生成作用的极大增强。同时给予脯氨酸类似物、血管抑制类固醇和肝素可完全抑制血管生成（100%的绒毛膜尿囊膜中存在无血管区），并且与之前使用类固醇-肝素组合观察到的无血管区相比，无血管区更大、更广泛。发现这些化合物（单独和组合）的抗血管生成作用与其抑制胶原蛋白积累的能力直接相关。已知改变ECM周转的额外化合物的筛选导致鉴定了新的血管生成抑制剂，全反式维甲酸。这些发现表明，生长中的毛细血管可能通过胶原代谢的改变而“切换”为退化模式，从而导致ECM结构完整性的丧失。确定ECM周转作为血管生成的主要控制点也可能为开发新的抗血管生成方案提供更合理的方法。
Combinations of angiostatic steroids and heparin induce basement membrane breakdown, capillary retraction, and endothelial cell rounding as part of their antiangiogenic action (Ingber DE, Madri JA, Folkman J: Endocrinology 119:1768, 1986). Specific modulators of matrix metabolism were examined for their effects and on capillary development in the growing chick chorioallantoic membrane to explore the possibility that structural alterations of extracellular matrix (ECM) could be causally involved in the antiangiogenic mechanism. Regression of growing capillaries was induced by proline analogs (1-azetidine-2-carboxylic acid, cis-hydroxyproline,d,L-3,4-dehydroproline, thioproline) and an inhibitor of prolyl hydroxylase (alpha,alpha-dipyridyl) which interfere with triple helix formation and prevent collagen deposition. Beta-aminopropionitrile, an inhibitor of collagen cross-linking, was also antiangiogenic although an inhibitor of glycosaminoglycan deposition (beta-methyl d-xyloside) was not. Combination of suboptimal doses of active collagen modulators with either angiostatic steroids or heparin resulted in great potentiation of their antiangiogenic effects. Coadministration of proline analogs, angiostatic steroids, and heparin resulted in complete inhibition of angiogenesis (avascular zones in 100% of chorioallantoic membranes) and larger and more extensive avascular zones than previously observed with steroid-heparin combinations. The antiangiogenic effects of these compounds (alone and in combination) were found to be directly related to their ability to inhibit collagen accumulation. Screening of additional compounds that are known to alter ECM turnover resulted in identification of a new angiogenesis inhibitor, all trans-retinoic acid. These findings suggest that growing capillaries may be "switched" into a regressive mode through alterations of collagen metabolism that result in loss of ECM structural integrity. Identification of ECM turnover as a major control point in angiogenesis may also provide a more rational approach for development of new antiangiogenic regimens.