Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

Abstract

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. 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. 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. 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.