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.

Absence of an anatomical origin for altered ductus venosus flow velocity waveforms in first‐trimester human fetuses with increased nuchal translucency

“…These findings imply a delay or disturbance in lymphatic development. This is consistent with prior morphological studies in euploid and aneuploid mouse embryos and human fetuses with nuchal edema . Limitations of this study include the impossibility to use healthy fetuses as controls.…”

“…Prior studies demonstrated the involvement of abnormal jugular lymphatic sacs (JLS) in increased NT . Specifically, an abnormal endothelial differentiation of blood endothelial cells towards lymphatic endothelial cells was observed in the JLS . Endothelial signaling plays an important role in embryonic development, such as in the formation of the heart, blood and lymphatic vasculature .…”

“…[30][31][32][33][34][35] Specifically, an abnormal endothelial differentiation of blood endothelial cells towards lymphatic endothelial cells was observed in the JLS. 34,36,37 Endothelial signaling plays an important role in embryonic development, such as in the formation of the heart, blood and lymphatic vasculature. 38 A disturbance in endothelial differentiation therefore may also lead to cardiac defects.…”

Molecular Signatures of Cardiac Defects in Down Syndrome Lymphoblastoid Cell Lines Suggest Altered Ciliome and Hedgehog Pathways

“…Among these signals, alteration in the level of Shh secreted by the pulmonary endoderm may affect the development of the atrial septum [53] , [54]. Interestingly, abnormal SHH expression has been observed in fetuses with DS presenting an increased nuchal translucency [55], a feature frequently associated with heart defects. Moreover, altered response to Shh is suggested to be associated to a deficit in neural crest development in Ts65Dn mice [56].…”

Angiogenic Gene Expression in Down Syndrome Fetal Hearts

“…VEGF genes also play a major role in the development of lymphatic endothelial cells from veins, and mutations in the VEGF -C allele cause lymph vessel dysfunction, severe systemic edema and lipid accumulation in bodily fluids [34]. Receptors for vascular endothelial growth factors (FLT4) are less abundant in lymphatic vessels of the skin of Turner fetuses indicating shortage of lymph capillaries [35], and VEGF-A expression has been correlated with aberrant lymphatic endothelial differentiation in trisomy 21 [36]. Interestingly, DS embryos have an increased NT whether or not they have heart anomalies.…”