Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis.
Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2(-/-) mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Helsinki University Central Hospital, University of Helsinki, Haartmaninkatu 8, P.O.B. 63, 00014 Helsinki, Finland.
Tatiana V
TV
Petrova
Terhi
T
Karpanen
Camilla
C
Norrmén
Russell
R
Mellor
Tomoki
T
Tamakoshi
David
D
Finegold
Robert
R
Ferrell
Dontscho
D
Kerjaschki
Peter
P
Mortimer
Seppo
S
Ylä-Herttuala
Naoyuki
N
Miura
Kari
K
Alitalo
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005070:Evans Blue; D051858:Forkhead Transcription Factors; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D042583:Lymphangiogenesis / Q000235:genetics*; D044148:Lymphatic Abnormalities / Q000235:genetics / Q000473:pathology*; D042601:Lymphatic Vessels / Q000473:pathology*; D008209:Lymphedema / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D020286:Pericytes / Q000473:pathology; D012313:RNA / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D005070:Evans Blue; D012313:RNA; D040321:Vascular Endothelial Growth Factor Receptor-3