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J Exp Med. 2017 Jul 19. pii: jem.20160875. doi: 10.1084/jem.20160875. [Epub ahead of print]

Human venous valve disease caused by mutations in FOXC2 and GJC2.

Author information

1
Academic Department of Vascular Surgery, Cardiovascular Division, BHF Centre of Research Excellence, King's College London, St Thomas' Hospital, London, England, UK oliver.lyons@kcl.ac.uk.
2
Academic Department of Vascular Surgery, Cardiovascular Division, BHF Centre of Research Excellence, King's College London, St Thomas' Hospital, London, England, UK.
3
Department of Ultrasonic Angiology, Guy's and St Thomas' NHS Foundation Trust, London, England, UK.
4
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA.
5
Harvard Medical School, Boston, MA.
6
Department of Fundamental Oncology, Ludwig Institute for Cancer Research, Zurich, Switzerland.
7
Division of Experimental Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Epalinges, Switzerland.
8
Center for Ultrastructural Imaging, King's College London, London, England, UK.
9
Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Evanston, IL.
10
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
11
South West Thames Regional Genetics Service, St George's Hospital, London, England, UK.
12
Cardiovascular and Cell Sciences Institute, St George's Hospital, London, England, UK.
13
Institute of Medical and Biomedical Education, St George's Hospital, London, England, UK.
14
Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
15
Academic Department of Vascular Surgery, Cardiovascular Division, BHF Centre of Research Excellence, King's College London, St Thomas' Hospital, London, England, UK alberto.smith@kcl.ac.uk.

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 Foxc2-Nfatc1 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.

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