Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S
Institute of Anatomy, University of Cologne, D-50931 Köln, Germany.
FASEB J. 2000 Dec;14(15):2373-6. doi: 10.1096/fj.00-0490fje.
Endostatin is a cleavage product of collagen XVIII that strongly inhibits tumor angiogenesis. To determine if endostatin affects other angiogenic processes, we generated full-thickness excisional wounds on the back of mice that were systemically treated with recombinant murine endostatin. No macroscopic abnormalities of the wound healing process were observed. Histological analysis revealed normal wound contraction and re-epithelialization, but a slight reduction in granulation tissue formation and reduced matrix deposition at the wound edge. The blood vessel density in the wounds of endostatin-treated mice was not affected. However, ultrastructural analysis demonstrated severe abnormalities in blood vessel maturation. The wound vessels in the endostatin-treated mice were narrowed or closed with an irregular luminal surface, resulting in a severe reduction in the number of functional vessels and extravasation of erythrocytes. Endostatin treatment did not affect the expression level and localization of collagen XVIII mRNA and protein. Furthermore, the angiogenesis regulators vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 were normally expressed in the wounds of endostatin-treated mice. However, expression of the major wound matrix proteins fibronectin and collagens I and III was significantly reduced. This reduction is likely to explain the reduced density of the wound matrix. Our results demonstrate that endostatin treatment reduces the number of functional blood vessels and the matrix density in the granulation tissue, but does not significantly affect the overall wound healing process.
内皮抑素是胶原蛋白 XVIII 的裂解产物，能强烈抑制肿瘤血管生成。为了确定内皮抑素是否影响其他血管生成过程，我们在经重组鼠内皮抑素全身治疗的小鼠背部制造了全层切除伤口。未观察到伤口愈合过程的宏观异常。组织学分析显示伤口正常收缩和重新上皮化，但肉芽组织形成略有减少，伤口边缘的基质沉积减少。内皮抑素治疗的小鼠伤口中的血管密度未受影响。然而，超微结构分析显示血管成熟存在严重异常。内皮抑素治疗的小鼠伤口血管变窄或闭合，管腔表面不规则，导致功能性血管数量严重减少和红细胞外渗。内皮抑素治疗不影响胶原蛋白 XVIII mRNA 和蛋白的表达水平及定位。此外，血管生成调节因子血管内皮生长因子、血管生成素 -1 和血管生成素 -2 在接受内皮抑素治疗的小鼠伤口中正常表达。然而，主要伤口基质蛋白纤连蛋白以及 I 型和 III 型胶原蛋白的表达显著降低。这种降低可能解释了伤口基质密度的降低。我们的结果表明，内皮抑素治疗减少了肉芽组织中功能性血管的数量和基质密度，但并未显著影响整体伤口愈合过程。
