Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system
Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system
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DOI：
10.1111/j.1749-6632.1997.tb52002.x
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发表时间：
1997-01-01
期刊：
影响因子：
--
通讯作者：
Collen, D
中科院分区：
文献类型：
--
作者：
Carmeliet, P;Moons, L;Collen, D
已经提出VEGF参与正常和病理性血管形成。令人惊讶的是，由于胚胎内和胚胎外血管的异常形成，仅缺乏单个VEGF等位基因导致胚胎死亡。由四倍体聚集产生的纯合子VEGF缺陷胚胎显示出更严重的血管形成缺陷。这些结果（1）表明VEGF对早期血管发育的严格调节，并间接地表明其他VEGF样分子的存在;（2）揭示了与常染色体基因杂合缺陷相关的前所未有的致死表型;（3）证明四倍体聚集是研究纯合VEGF缺陷胚胎表型的有效和唯一方法。VEGF在体内的主要和严格的剂量依赖性作用使该分子成为促进或预防血管生成的理想治疗靶点。组织因子（TF）是凝血的主要细胞起始因子，其表达失调与脓毒症、癌症和炎症中的血栓形成有关。然而，TF似乎也参与多种非止血功能，包括炎症、癌症、脑功能、免疫应答和肿瘤相关血管生成。令人惊讶的是，TF缺乏导致胚胎死亡，由于异常的胚外血管发育和缺陷的卵黄胚胎循环。异常的卵黄囊脉管系统让人想起在缺乏VEGF的胚胎中观察到的，可能表明这两种基因功能是相互关联的。这些靶向研究扩展了最近记录的TF在肿瘤相关血管生成中的作用，并保证进一步研究其在其他病理性疾病中的血管生成作用。纤溶酶原系统通过其触发物组织型纤溶酶原激活物（t-PA）和尿激酶型纤溶酶原激活物（u-PA）及其抑制剂纤溶酶原激活物抑制剂-1（派-1）参与血栓形成、动脉新生内膜形成和动脉粥样硬化。对t-PA、u-PA、派-1、尿激酶受体（u-PAR）和纤溶酶原（Plg）靶基因失活小鼠的研究表明：（1）t-PA或u-PA缺乏可增加炎症相关血栓形成的易感性，t-PA：u-PA联合缺乏或Plg缺乏可引起严重的自发性血栓形成;（2）在u-PA介导的纤溶酶蛋白水解缺乏的小鼠中，血管损伤诱导的新生内膜形成减少，在t-PA或u-PAR缺乏的小鼠中不改变，而在派-1缺乏的小鼠中加速，但腺病毒派-1基因转移可以逆转血管损伤诱导的新生内膜形成;和（3）在富含胆固醇的饮食10周后，载脂蛋白E（apoE）和派-1双重缺陷小鼠的动脉粥样硬化减少。因此，纤溶酶原系统显著影响血栓形成、再狭窄和动脉粥样硬化。
VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra-and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules;(2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitelloembryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA: u-PA or deficiency of Plg induces severe spontaneous thrombosis;(2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA-or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.