Nuchal edema and venous-lymphatic phenotype disturbance in human fetuses and mouse embryos with aneuploidy.
OBJECTIVE
Nuchal edema (NE) is a clinical indicator for aneuploidy, cardiovascular anomalies, and several genetic syndromes. Its etiology, however, is unknown. In the nuchal area, the endothelium of the jugular lymphatic sacs (JLS) develops by budding from the blood vascular endothelium of the cardinal veins. Abnormal distension of the jugular sacs is associated with NE. We hypothesize that a disturbed lymphatic endothelial differentiation and sac formation causes NE. We investigated endothelial differentiation of the jugular lymphatic system in human and mouse species with NE.


METHODS
Aneuploid human fetuses (trisomy 21; trisomy 18) were compared with euploid controls (gestational age 12 to 18 weeks). Trisomy 16 mouse embryos were compared with wild type controls (embryonic day 10 to 18). Trisomy 16 mice are considered an animal model for human trisomy 21. Endothelial differentiation was investigated by immunohistochemistry using lymphatic markers (prox-1, podoplanin, lymphatic vessel endothelial hyaluronan receptor [LYVE]-1) and en blood vessel markers (neuropilin [NP]-1 and ligand vascular endothelial growth factor [VEGF]-A). Smooth muscle actin (SMA) was included as a smooth muscle cell marker.


RESULTS
We report a disturbed venous-lymphatic phenotype in aneuploid human fetuses and mouse embryos with enlarged jugular sacs and NE. Our results show absent or diminished expression of the lymphatic markers Prox-1 and podoplanin in the enlarged jugular sac, while LYVE-1 expression was normal. Additionally, the enlarged JLS showed blood vessel characteristics, including increased NP-1 and VEGF-A expression. The lumen contained blood cells and smooth muscle cells lined the wall.


CONCLUSIONS
A loss of lymphatic identity seems to be the underlying cause for clinical NE. Also, abnormal endothelial differentiation provides a link to the cardiovascular anomalies associated with NE.
Bekker
Mireille N
MN
Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
van den Akker
Nynke M S
NM
Bartelings
Margot M
MM
Arkesteijn
Jenny B
JB
Fischer
Sigrid G L
SG
Polman
Japke A E
JA
Haak
Monique C
MC
Webb
Sandra
S
Poelmann
Robert E
RE
van Vugt
John M G
JM
Gittenberger-de Groot
Adriana C
AC
D000782:Aneuploidy; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004487:Edema / Q000235:genetics* / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000196:embryology*; D042783:Endothelial Cells; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000196:embryology*; D005333:Fetus / Q000196:embryology*; D018398:Homeodomain Proteins / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D051379:Mice; D009333:Neck / Q000196:embryology / Q000473:pathology; D048208:Nuchal Translucency Measurement; D010641:Phenotype; D012867:Skin / Q000196:embryology / Q000473:pathology; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein
D015415:Biomarkers; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein