Human venous valve disease caused by mutations in FOXC2 and GJC2

被引：30

作者：

Lyons, Oliver ^{[1
]}

Saha, Prakash ^{[1
]}

Seet, Christopher ^{[1
]}

Kuchta, Adam ^{[3
]}

Arnold, Andrew ^{[3
]}

Grover, Steven ^{[4
,5
]}

Rashbrook, Victoria ^{[1
]}

Sabine, Amelie ^{[6
,7
]}

Vizcay-Barrena, Gema ^{[2
]}

Patel, Ash ^{[1
]}

Ludwinski, Francesca ^{[1
]}

Padayachee, Soundrie ^{[3
]}

Kume, Tsutomu ^{[8
]}

Kwak, Brenda R. ^{[9
]}

Brice, Glen ^{[10
]}

Mansour, Sahar ^{[10
]}

Ostergaard, Pia ^{[11
]}

Mortimer, Peter ^{[11
]}

Jeffery, Steve ^{[11
]}

Brown, Nigel ^{[12
]}

Makinen, Taija ^{[13
]}

Petrova, Tatiana V. ^{[6
,7
]}

Modarai, Bijan ^{[1
]}

Smith, Alberto ^{[1
]}

机构：

[1] St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England

[2] Kings Coll London, Ctr Ultrastruct Imaging, London, England

[3] Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England

[4] Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA

[5] Harvard Med Sch, Boston, MA USA

[6] Ludwig Inst Canc Res, Dept Fundamental Oncol, Zurich, Switzerland

[7] Univ Lausanne, Div Expt Pathol, Ctr Hosp Univ Vaudois, Epalinges, Switzerland

[8] Northwestern Univ, Sch Med, Feinberg Cardiovasc Res Inst, Evanston, IL USA

[9] Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland

[10] St George Hosp, South West Thames Reg Genet Serv, London, England

[11] St George Hosp, Cardiovasc & Cell Sci Inst, London, England

[12] St George Hosp, Inst Med & Biomed Educ, London, England

[13] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 08期

基金：

英国医学研究理事会;

关键词：

LYMPHEDEMA-DISTICHIASIS SYNDROME; LYMPHATIC VESSEL MATURATION; TRANSCRIPTION FACTOR; ENDOTHELIAL-CELLS; UNEXPECTED ROLE; CONNEXIN; 37; LOWER-LIMB; IN-VIVO; MICE; VEINS;

D O I：

10.1084/jem.20160875

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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 Prox1(hi) 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 Prox1(hi) endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1(hi) 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 Prox1(hi) 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.

引用

页码：2437 / 2452

页数：16

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