Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes
Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes
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DOI：
10.1096/fj.01-1042com
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发表时间：
2002-07-01
期刊：
影响因子：
4.8
通讯作者：
Alitalo, K
中科院分区：
文献类型：
--
作者：
Saaristo, A;Veikkola, T;Alitalo, K
血管内皮生长因子（VEGF）及其受体（VEGF受体）是血管和淋巴管生长和血管通透性的重要调节因子。VEGF-C/VEGFR-3信号通路对于淋巴管生成至关重要，并且VEGFR-3基因的杂合失活错义突变与遗传性水肿相关。然而，VEGF-C可以对血管具有有效的作用，因为其受体VEGFR-3在某些血管中表达，并且因为VEGF-C的完全加工形式也与血管的VEGFR-2结合。为了表征VEGF-C对血管和淋巴管的体内作用，我们通过腺病毒和腺相关病毒介导的转染在无胸腺裸鼠的皮肤和呼吸道中过表达VEGF-C。这导致静脉的剂量依赖性增大和弯曲，发现静脉沿着集合淋巴管表达VEGFR-2。血管生成素1的表达阻断了VEGF-C诱导的血管渗漏增加，而血管扩张和淋巴管生成不受影响。然而，没有观察到新血管的血管生成发芽响应于AdVEGF-C或AAV-VEGF-C。这些结果表明，病毒产生的VEGF-C诱导血管变化，包括血管渗漏，但与正常皮肤中的VEGF相比，其血管生成效力大大降低。
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin.