title: Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency.
abstract: OBJECTIVE
  Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)-A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF-A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet-derived growth factor (PDGF)-B in the lymphatic endothelial cells of the JLS.
  
  
  METHODS
  Five trisomy 21 fetuses and four controls were investigated using immunohistochemistry for Shh, VEGF-A, FOXC2 and PDGF-B expression in the lymphatic endothelial cells of the JLS.
  
  
  RESULTS
  An increased Shh, VEGF-A and PDGF-B expression, and decreased FOXC2 expression were shown in the lymphatic endothelial cells of the JLS of the trisomic fetuses.
  
  
  CONCLUSIONS
  Increased Shh and VEGF-A expression is correlated with an aberrant lymphatic endothelial differentiation in trisomy 21 fetuses. The SMCs surrounding the JLS can possibly be explained by an increase of PDGF-B-induced SMC recruitment and/or differentiation. This underscores earlier findings that indicate the loss of lymphatic identity in trisomy 21 fetuses and a shift towards a blood vessel wall phenotype.
authors: Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors: Yolanda M
authors: YM
authors: de Mooij
authors: Nynke M S
authors: NM
authors: van den Akker
authors: Mireille N
authors: MN
authors: Bekker
authors: Margot M
authors: MM
authors: Bartelings
authors: Lambertus J
authors: LJ
authors: Wisse
authors: John M G
authors: JM
authors: van Vugt
authors: Adriana C
authors: AC
authors: Gittenberger-de Groot
mesh_terms: D015415:Biomarkers / Q000032:analysis; D001808:Blood Vessels / Q000378:metabolism; D004314:Down Syndrome / Q000175:diagnosis / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000502:physiology; D005318:Fetal Heart / Q000033:anatomy & histology; D005333:Fetus / Q000002:abnormalities / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008208:Lymphatic System / Q000002:abnormalities* / Q000196:embryology* / Q000378:metabolism; D042601:Lymphatic Vessels / Q000196:embryology / Q000378:metabolism; D009333:Neck / Q000196:embryology; D048208:Nuchal Translucency Measurement; D011247:Pregnancy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; C509239:SHH protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C082078:mesenchyme fork head 1 protein