Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3

T Mäkinen; T Veikkola; S Mustjoki; T Karpanen; B Catimel; E C Nice; L Wise; A Mercer; H Kowalski; D Kerjaschki; S A Stacker; M G Achen; K Alitalo

doi:10.1093/emboj/20.17.4762

Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3

EMBO J. 2001 Sep 3;20(17):4762-73. doi: 10.1093/emboj/20.17.4762.

Authors

T Mäkinen¹, T Veikkola, S Mustjoki, T Karpanen, B Catimel, E C Nice, L Wise, A Mercer, H Kowalski, D Kerjaschki, S A Stacker, M G Achen, K Alitalo

Affiliation

¹ Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, and Helsinki University Hospital, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland.

Abstract

Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Apoptosis / physiology*
Biosensing Techniques
Capillaries / embryology
Capillaries / physiology
Cell Division
Cell Movement
Cell Survival
Cells, Cultured
Endothelial Growth Factors / pharmacology*
Endothelial Growth Factors / physiology*
Endothelium / cytology
Endothelium / physiology*
Endothelium, Vascular / cytology
Endothelium, Vascular / physiology*
Enzyme Activation
Humans
Kinetics
Lymphatic System / cytology
Lymphatic System / physiology*
MAP Kinase Signaling System / physiology*
Microcirculation / physiology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / metabolism
Protein Kinase C / metabolism
RNA, Messenger / genetics
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / physiology*
Receptors, Growth Factor / genetics
Receptors, Growth Factor / physiology*
Receptors, Vascular Endothelial Growth Factor
Skin / blood supply
Umbilical Veins
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor D
Vascular Endothelial Growth Factor Receptor-3

Substances

Endothelial Growth Factors
RNA, Messenger
Receptors, Growth Factor
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor D
Receptor Protein-Tyrosine Kinases
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor Receptor-3
Protein Kinase C
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases