Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation.
During embryonic development, lymph sacs form from the cardinal vein, and sprout centrifugally to form mature lymphatic networks. Separation of the lymphatic from the blood circulation by a hitherto unknown mechanism is essential for the homeostatic function of the lymphatic system. O-glycans on the lymphatic endothelium have recently been suggested to be required for establishment and maintenance of distinct blood and lymphatic systems, primarily by mediating proper function of podoplanin. Here, we show that this separation process critically involves platelet activation by podoplanin. We found that platelet aggregates build up in wild-type embryos at the separation zone of podoplanin(+) lymph sacs and cardinal veins, but not in podoplanin(-/-) embryos. Thus, podoplanin(-/-) mice develop a "nonseparation" phenotype, characterized by a blood-filled lymphatic network after approximately embryonic day 13.5, which, however, partially resolves in postnatal mice. The same embryonic phenotype is also induced by treatment of pregnant mice with acetyl salicylic acid, podoplanin-blocking antibodies, or by inactivation of the kindlin-3 gene required for platelet aggregation. Therefore, interaction of endothelial podoplanin of the developing lymph sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system.
Uhrin
Pavel
P
Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
Zaujec
Jan
J
Breuss
Johannes M
JM
Olcaydu
Damla
D
Chrenek
Peter
P
Stockinger
Hannes
H
Fuertbauer
Elke
E
Moser
Markus
M
Haiko
Paula
P
Fässler
Reinhard
R
Alitalo
Kari
K
Binder
Bernd R
BR
Kerjaschki
Dontscho
D
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology*; D001808:Blood Vessels / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007124:Immunoenzyme Techniques; D042601:Lymphatic Vessels / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation; D011247:Pregnancy; D020156:Salicylic Acid / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology; D000098853:Podoplanin
D000890:Anti-Infective Agents; D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D020156:Salicylic Acid; D040321:Vascular Endothelial Growth Factor Receptor-3; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C527818:kindlin-3 protein, mouse