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Human venous valve disease caused by mutations in FOXC2 and GJC2

Lyons, Oliver (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Saha, Prakash (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Seet, Christopher (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
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Kuchta, Adam (author)
Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England
Arnold, Andrew (author)
Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England
Grover, Steven (author)
Harvard Med Sch, Boston, MA USA;Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA
Rashbrook, Victoria (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Sabine, Amelie (author)
Univ Lausanne, Div Expt Pathol, Ctr Hosp Univ Vaudois, Epalinges, Switzerland;Ludwig Inst Canc Res, Dept Fundamental Oncol, Zurich, Switzerland
Vizcay-Barrena, Gema (author)
Kings Coll London, Ctr Ultrastruct Imaging, London, England
Patel, Ash (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Ludwinski, Francesca (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Padayachee, Soundrie (author)
Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England
Kume, Tsutomu (author)
Northwestern Univ, Sch Med, Feinberg Cardiovasc Res Inst, Evanston, IL USA
Kwak, Brenda R. (author)
Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland
Brice, Glen (author)
St George Hosp, South West Thames Reg Genet Serv, London, England
Mansour, Sahar (author)
St George Hosp, South West Thames Reg Genet Serv, London, England
Ostergaard, Pia (author)
St George Hosp, Cardiovasc & Cell Sci Inst, London, England
Mortimer, Peter (author)
St George Hosp, Cardiovasc & Cell Sci Inst, London, England
Jeffery, Steve (author)
St George Hosp, Cardiovasc & Cell Sci Inst, London, England
Brown, Nigel (author)
St George Hosp, Inst Med & Biomed Educ, London, England
Mäkinen, Taija (author)
Uppsala universitet,Vaskulärbiologi
Petrova, Tatiana V. (author)
Univ Lausanne, Div Expt Pathol, Ctr Hosp Univ Vaudois, Epalinges, Switzerland;Ludwig Inst Canc Res, Dept Fundamental Oncol, Zurich, Switzerland
Modarai, Bijan (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
Smith, Alberto (author)
St Thomas Hosp, Acad Dept Vasc Surg, Cardiovasc Div, BHF Ctr Res Excellence,Kings Coll London, London, England
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 (creator_code:org_t)
2017-07-19
2017
English.
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 214:8, s. 2437-2452
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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