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 Brown; Taija Makinen; Tatiana V. Petrova; Bijan Modarai; Alberto Smith

doi:10.1084/jem.20160875

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

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

29 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 language	English (US)
Pages (from-to)	2437-2452
Number of pages	16
Journal	Journal of Experimental Medicine
Volume	214
Issue number	8
DOIs	https://doi.org/10.1084/jem.20160875
State	Published - Aug 1 2017

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ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1084/jem.20160875

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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

@article{17fd7862b99846cebcf34545fbe9bd16,

title = "Human venous valve disease caused by mutations in FOXC2 and GJC2",

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.",

author = "Oliver Lyons and Prakash Saha and Christopher Seet and Adam Kuchta and Andrew Arnold and Steven Grover and Victoria Rashbrook and Am{\'e}lie Sabine and Gema Vizcay-Barrena and Ash Patel and Francesca Ludwinski and Soundrie Padayachee and Tsutomu Kume and Kwak, {Brenda R.} and Glen Brice and Sahar Mansour and Pia Ostergaard and Peter Mortimer and Steve Jeffery and Nigel Brown and Taija Makinen and Petrova, {Tatiana V.} and Bijan Modarai and Alberto Smith",

note = "Publisher Copyright: {\textcopyright} 2017 Lyons et al.",

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month = aug,

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doi = "10.1084/jem.20160875",

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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, BR, Brice, G, Mansour, S, Ostergaard, P, Mortimer, P, Jeffery, S, Brown, N, Makinen, T, Petrova, TV, Modarai, B & Smith, A 2017, 'Human venous valve disease caused by mutations in FOXC2 and GJC2', Journal of Experimental Medicine, vol. 214, no. 8, pp. 2437-2452. https://doi.org/10.1084/jem.20160875

TY - JOUR

T1 - Human venous valve disease caused by mutations in FOXC2 and GJC2

AU - Lyons, Oliver

AU - Saha, Prakash

AU - Seet, Christopher

AU - Kuchta, Adam

AU - Arnold, Andrew

AU - Grover, Steven

AU - Rashbrook, Victoria

AU - Sabine, Amélie

AU - Vizcay-Barrena, Gema

AU - Patel, Ash

AU - Ludwinski, Francesca

AU - Padayachee, Soundrie

AU - Kume, Tsutomu

AU - Kwak, Brenda R.

AU - Brice, Glen

AU - Mansour, Sahar

AU - Ostergaard, Pia

AU - Mortimer, Peter

AU - Jeffery, Steve

AU - Brown, Nigel

AU - Makinen, Taija

AU - Petrova, Tatiana V.

AU - Modarai, Bijan

AU - Smith, Alberto

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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DO - 10.1084/jem.20160875

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JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 8

ER -

Human venous valve disease caused by mutations in FOXC2 and GJC2

Abstract

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ASJC Scopus subject areas

UN SDGs

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