Saturday, April 15, 2006

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


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

Dagenais SL, Hartsough RL, Erickson RP, Witte MH, Butler MG, Glover TW.

Department of Human Genetics, University of Michigan, 4909 Buhl, Box 0618, 1241 E. Catherine Street, Ann Arbor, MI 48109-0618, USA.

The molecular events involved in lymphatic development are poorly understood. Hence, the genes responsible for hereditary lymphedema are of great interest due to the potential for providing insights into the mechanisms of lymphatic development, the diagnosis, prevention and treatment of lymphedema, and lymphangiogenesis during tumor growth.

Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome. We have conducted a study of Foxc2 expression during mouse development using immunohistochemistry, and examined its expression in lymphatics compared to its paralog Foxc1 and to Vegfr-3, Prox1 and other lymphatic and blood vascular proteins. We have found that Foxc2 is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors and capillaries, as well as in podocytes, developing eyelids and other tissues associated with abnormalities in lymphedema-distichiasis syndrome.

PMID: 15465483

[PubMed - indexed for MEDLINE]

For further information:

Truncating mutations in FOXC2 cause multiple lymphedema syndromes.

Full Text Article

FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome.

Full Text Article

Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome.

Full Text Article

1 comment:

Jellybean454545 said...

That is great information. Thank you. I have primary lymphedema - as does my father and his two sisters and his father had it as well. Neither of my daughters have shown signs but, they both have distichiasis like I do. **sigh** Guess I know what's in store for them. Thank you so much for this information.