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Article
Nature Medicine  10, 974 - 981 (2004)
Published online: 22 August 2004; | doi:10.1038/nm1094

Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis

Tatiana V Petrova1, 8, Terhi Karpanen1, 8, Camilla Norrmén1, Russell Mellor2, Tomoki Tamakoshi3, David Finegold4, 5, Robert Ferrell4, Dontscho Kerjaschki6, Peter Mortimer6, Seppo Ylä-Herttuala7, Naoyuki Miura3 & Kari Alitalo1

1  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.

2  Dermatology Unit, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK.

3  Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

4  Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

5  Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

6  Department of Pathology, University of Vienna Medical School, 1090 Vienna, Austria.

7  A.I.Virtanen Institute, University of Kuopio, P.O.B. 1627, 70211 Kuopio, Finland.

8  These authors contributed equally to this work.

Correspondence should be addressed to Kari Alitalo kari.alitalo@helsinki.fi
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.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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