Transgenic Induction of Vascular Endothelial Growth Factor-C Is Strongly Angiogenic in Mouse Embryos but Leads to Persistent Lymphatic Hyperplasia in Adult Tissues
Transgenic Induction of Vascular Endothelial Growth Factor-C Is Strongly Angiogenic in Mouse Embryos but Leads to Persistent Lymphatic Hyperplasia in Adult Tissues
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DOI：
10.2353/ajpath.2008.080378
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发表时间：
2008-12-01
影响因子：
6
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
--
作者：
Lohela, Marja;Helotera, Hanna;Alitalo, Kari
血管内皮生长因子-C（VEGF-C）是淋巴系统发育所需的典型淋巴管生成生长因子，能够通过激活其受体VEGFR-3刺激成人淋巴管生成。虽然VEGF-C是一个主要的候选分子，用于开发淋巴管生成前治疗有缺陷的淋巴管水肿，稳定性的淋巴管产生的外源性VEGF-C管理目前还不知道。我们在诱导型转基因小鼠模型中研究了VEGF-C刺激的淋巴管生成，在该模型中生长因子的表达可以在空间和时间上得到控制，而没有副作用，如炎症。在成年小鼠皮肤中诱导VEGF-C 1至2周引起持续至少6个月的强烈淋巴增生。当VEGF-C在新生小鼠或成年小鼠的血管内皮中表达时，在许多组织和器官中诱导淋巴管生成。在血管或集合淋巴管中观察到很少或没有影响。此外，VEGF-C刺激淋巴管发育开始后胚胎中的淋巴管生成。引人注目的是，在胚胎第16.5天之前的任何时间点，在血管内皮中VEGF-C诱导后观察到强烈的血管生成作用。我们的研究结果表明，即使胚胎中VEGFR-3下调，血管也可以经历VEGF诱导的血管生成;然而，成人中的短暂VEGF-C表达可以诱导持久的淋巴管增生，对血管系统没有明显的副作用。(Am J Pathol 2008，173：1891-1901; DOI：10.2353/ajpath.2008.080378）
Vascular endothelial growth factor-C (VEGF-C) is the quintessential lymphangiogenic growth factor that is required for the development of the lymphatic system and is capable of stimulating lymphangiogenesis in adults by activating its receptor, VEGFR-3. Although VEGF-C is a major candidate molecule for the development of prolymphangiogenic therapy for defective lymphatic vessels in lymphedema, the stability of lymph vessels generated by exogenous VEGF-C administration is not currently known. We studied VEGF-C-stimulated lymphangiogenesis in inducible transgenic mouse models in which growth factor expression can be spatially and temporally controlled without side effects, such as inflammation. VEGF-C induction in adult mouse skin for 1 to 2 weeks caused robust lymphatic hyperplasia that persisted for at least 6 months. VEGF-C induced lymphangiogenesis in numerous tissues and organs when expressed in the vascular endothelium in either neonates or adult mice. Very few or no effects were observed in either blood vessels or collecting lymph vessels. Additionally, VEGF-C stimulated lymphangiogenesis in embryos after the onset of lymphatic vessel development. Strikingly, a strong angiogenic effect was observed after VEGF-C induction in vascular endothelium at any point before embryonic day 16.5. Our results indicate that blood vessels can undergo VEGFG-induced angiogenesis even after down-regulation of VEGFR-3 in embryos; however, transient VEGF-C expression in adults can induce long-lasting lymphatic hyperplasia with no obvious side effects on the blood vasculature. (Am J Pathol 2008, 173:1891-1901; DOI: 10.2353/ajpath.2008.080378)