Signalling via vascular endothelial growth factor receptor-3 is sufficientfor lymphangiogenesis in transgenic mice

Vascular endothelial growth factor receptor-3 (VEGFR-3) has an essential ro le in the development of embryonic blood vessels; however, after midgestati on its expression becomes restricted mainly to the developing lymphatic ves sels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, w hich is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which bi nds to the same receptors, has been reported to induce angiogenesis, but it s lymphangiogenic potential is not known, In order to define the lymphangio genic signalling pathway we have created transgenic mice overexpressing a V EGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal kerati nocytes under the keratin 14 promoter. Both transgenes induced the growth o f 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 irt vivo. These results demonstrate that stimulation of t he VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo.