Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin.
Podoplanin is a small transmembrane protein required for development and function of the lymphatic vascular system. To investigate the effects of interfering with its function, we produced an Fc fusion protein of its ectodomain. We found that podoplanin-Fc inhibited several functions of cultured lymphatic endothelial cells and also specifically suppressed lymphatic vessel growth, but not blood vessel growth, in mouse embryoid bodies in vitro and in mouse corneas in vivo. Using a keratin 14 expression cassette, we created transgenic mice that overexpressed podoplanin-Fc in the skin. No obvious outward phenotype was identified in these mice, but surprisingly, podoplanin-Fc-although produced specifically in the skin-entered the blood circulation and induced disseminated intravascular coagulation, characterized by microthrombi in most organs and by thrombocytopenia, occasionally leading to fatal hemorrhage. These findings reveal an important role of podoplanin in lymphatic vessel formation and indicate the potential of podoplanin-Fc as an inhibitor of lymphangiogenesis. These results also demonstrate the ability of podoplanin to induce platelet aggregation in vivo, which likely represents a major function of lymphatic endothelium. Finally, keratin 14 podoplanin-Fc mice represent a novel genetic animal model of disseminated intravascular coagulation.
Cueni
Leah N
LN
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Chen
Lu
L
Zhang
Hui
H
Marino
Daniela
D
Huggenberger
Reto
R
Alitalo
Annamari
A
Bianchi
Roberta
R
Detmar
Michael
M
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D003315:Cornea / Q000473:pathology; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D058732:Embryoid Bodies / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053547:Keratin-14 / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D015539:Platelet Activation; D011485:Protein Binding; D011961:Receptors, Fc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology*; D000098853:Podoplanin
D053547:Keratin-14; D008562:Membrane Glycoproteins; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C117468:PDPN protein, human; D000098853:Podoplanin