Karelina T V, Goldberg G I, Eisen A Z
Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Invest Dermatol. 1995 Sep;105(3):411-7. doi: 10.1111/1523-1747.ep12321097.
In vitro angiogenesis models suggest that new blood vessel formation requires the induction and secretion by endothelial cells of matrix metalloproteinases. These enzymes assist in the controlled proteolytic degradation of the surrounding extracellular matrix during blood vessel formation. The results of in vitro studies cannot be extrapolated directly to the process of in vivo angiogenesis because the type of matrix employed and the repertoire of enzymes secreted by cells in vivo differ dramatically from in vivo conditions. To investigate the in vivo role of matrix metalloproteinases in blood vessel development, we looked for the presence of these proteinases in endothelial cells involved in fetal angiogenesis and in neovascularization of certain invasive skin tumors using immunofluorescent staining. In fetal tissue, interstitial collagenase was present in both early microvessels developing from undifferentiated mesoderm and in microvessels involved in elongation and sprout formation from preexisting blood vessels. In aggressive skin tumors, i.e., morpheaform and recurrent basal cell carcinomas and squamous cell carcinomas, there was a marked increase in the number of collagenase-containing blood vessels, often extending into the tumor nests. Immunofluorescent staining failed to detect stromelysin, matrilysin, or gelatinase A and B (72- and 92-kDa type IV collagenases, respectively) in fetal or tumor blood vessels. These findings are consistent with the hypothesis that proteolytic degradation of the extracellular matrix is required for the formation of new blood vessels. Interstitial collagenase appears to play an important role in this process.
体外血管生成模型表明，新血管形成需要内皮细胞诱导并分泌基质金属蛋白酶。这些酶在血管形成过程中有助于对周围细胞外基质进行可控的蛋白水解降解。体外研究结果不能直接外推至体内血管生成过程，因为体内使用的基质类型以及细胞分泌的酶种类与体外条件差异极大。为了研究基质金属蛋白酶在血管发育中的体内作用，我们利用免疫荧光染色法，寻找这些蛋白酶在参与胎儿血管生成的内皮细胞以及某些侵袭性皮肤肿瘤新生血管中的存在情况。在胎儿组织中，间质胶原酶既存在于由未分化中胚层发育而来的早期微血管中，也存在于参与已有血管伸长和芽生形成的微血管中。在侵袭性皮肤肿瘤，即硬斑病样及复发性基底细胞癌和鳞状细胞癌中，含胶原酶的血管数量显著增加，且常常延伸至肿瘤巢内。免疫荧光染色未能在胎儿或肿瘤血管中检测到基质溶解素、基质溶素或明胶酶A和B（分别为72 kDa和92 kDa的IV型胶原酶）。这些发现与细胞外基质的蛋白水解降解是新血管形成所必需的这一假说相符。间质胶原酶似乎在这一过程中发挥着重要作用。
