Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova T V, Kubo H, Thurston G, McDonald D M, Achen M G, Stacker S A, Alitalo K
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, PO Box 21 (Haartmaninkatu 3), 00014 Helsinki, Finland.
EMBO J. 2001 Mar 15;20(6):1223-31. doi: 10.1093/emboj/20.6.1223.
Vascular endothelial growth factor receptor-3 (VEGFR-3) has an essential role in the development of embryonic blood vessels; however, after midgestation its expression becomes restricted mainly to the developing lymphatic vessels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which binds to the same receptors, has been reported to induce angiogenesis, but its lymphangiogenic potential is not known. In order to define the lymphangiogenic signalling pathway we have created transgenic mice overexpressing a VEGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal keratinocytes under the keratin 14 promoter. Both transgenes induced the growth of lymphatic vessels in the skin, whereas the blood vessel architecture was not affected. Evidence was also obtained that these growth factors act in a paracrine manner in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.
血管内皮生长因子受体-3（VEGFR-3）在胚胎血管发育中起关键作用；然而，妊娠中期后其表达主要局限于发育中的淋巴管。VEGFR-3配体VEGF-C在转基因小鼠和鸡胚绒毛尿囊膜中刺激淋巴管生成。由于VEGF-C也结合淋巴管内皮细胞中表达的VEGFR-2，因此尚不清楚哪些受体负责VEGF-C的淋巴管生成作用。据报道，与相同受体结合的VEGF-D可诱导血管生成，但其淋巴管生成潜力尚不清楚。为了确定淋巴管生成信号通路，我们构建了在角蛋白14启动子控制下在表皮角质形成细胞中过表达VEGF-C（VEGF-C156S）或VEGF-D的VEGFR-3特异性突变体的转基因小鼠。两种转基因均诱导皮肤中淋巴管的生长，而血管结构未受影响。还获得证据表明这些生长因子在体内以旁分泌方式起作用。这些结果表明，刺激VEGFR-3信号转导通路足以在体内特异性诱导淋巴管生成。
