OBJECTIVE Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60–70% of the Noonan syndrome... Show moreOBJECTIVE Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60–70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation. METHOD Fetuses with increased NT and normal karyotype (n = 7) were compared with euploid controls having normal NT (n = 5). A Noonan syndrome gene mutation was found in three out of seven fetuses with increased NT. Endothelial differentiation was evaluated by immunohistochemistry using lymphatic markers (PROX-1, Podoplanin, LYVE-1) and blood vessel markers vascular endothelial growth factor-A (VEGF-A), Neuropilin-1 (NP-1), Sonic hedgehog, von Willebrand factor, and the smooth muscle cell marker, smooth muscle actin. RESULTS Nuchal edema and enlarged jugular lymphatic sacs (JLSs) were observed in fetuses with increased NT, together with abnormal lymphatic endothelial differentiation i.e. the presence of blood vessel characteristics, including high levels of VEGF-A and NP-1 expression. The enlarged JLSs contained erythrocytes and were surrounded by smooth muscle cells. CONCLUSION This study shows an aberrant lymphatic endothelial differentiation in fetuses with increased NT and a normal karyotype (including Noonan syndrome fetuses), as was previously reported before in aneuploid fetuses. Show less
The central cell type within vascular development is the endothelial cell (EC). It forms during (lymph)vasculogenesis, proliferates during angiogenesis and instructs medial cells during... Show moreThe central cell type within vascular development is the endothelial cell (EC). It forms during (lymph)vasculogenesis, proliferates during angiogenesis and instructs medial cells during arteriogenesis. The venous population also gives rise to a subset of the lymphatic endothelium and the endocardium is instructive in formation of the primitive heart. We show that endothelial plasticity is very high in the developing embryo/fetus and that its outcome is dependent on the VEGF, Notch and PDGF-signaling pathways. Alterations in VEGF and Notch-signaling abrogate endocardial and endothelial differentiation, cardiac development and coronary maturation. Alterations in these pathways are most likely also involved in abnormal lymphatic development as seen in fetuses with increased nuchal translucency. In this thesis, lymphatic endothelial plasticity is particularly underscored, as lymphatic ECs gain arterial characteristics in certain pathological situations. Additionally, we show that impaired VEGF, Notch and PDGF-B/PDGFR-_-signaling in ECs and/or vSMCs severely impairs coronary arteriogenesis. In conclusion, many growth factors either influencing the EC (such as VEGF) or produced by the EC (such as PDGF) play a role in regulating and fine-tuning these processes. Increasing our knowledge on how these factors influence (ab)normal vascular development will improve our understanding of many pathological conditions and might increase therapeutic approaches. Show less
