Human venous valve disease caused by mutations in FOXC2 and GJC2

Oliver Lyons*, Prakash Saha, Christopher Seet, Adam Kuchta, Andrew Arnold, Steven Grover, Victoria Rashbrook, Amélie Sabine, Gema Vizcay-Barrena, Ash Patel, Francesca Ludwinski, Soundrie Padayachee, Tsutomu Kume, Brenda R. Kwak, Glen Brice, Sahar Mansour, Pia Ostergaard, Peter Mortimer, Steve Jeffery, Nigel BrownTaija Makinen, Tatiana V. Petrova, Bijan Modarai, Alberto Smith

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation (organization) of Prox1hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1hi endothelial organization, suggesting cooperative Foxc2Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1hi endothelial organization at postnatal day 0, and this likely underlies the VV defects seen in patients with GJC2 mutations. Knockout of Gja4 or Gjc2 resulted in reduced proliferation of Prox1hi valve-forming cells. At later stages of blood flow, Foxc2 and calcineurin-Nfat signaling are each required for growth of the valve leaflets, whereas Foxc2 is not required for VV maintenance.

Original languageEnglish (US)
Pages (from-to)2437-2452
Number of pages16
JournalJournal of Experimental Medicine
Volume214
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lyons, O., Saha, P., Seet, C., Kuchta, A., Arnold, A., Grover, S., Rashbrook, V., Sabine, A., Vizcay-Barrena, G., Patel, A., Ludwinski, F., Padayachee, S., Kume, T., Kwak, B. R., Brice, G., Mansour, S., Ostergaard, P., Mortimer, P., Jeffery, S., ... Smith, A. (2017). Human venous valve disease caused by mutations in FOXC2 and GJC2. Journal of Experimental Medicine, 214(8), 2437-2452. https://doi.org/10.1084/jem.20160875