An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation.
BACKGROUND
Lymphatic vasculature plays important roles in tissue fluid homeostasis maintenance and in the pathology of human diseases. Yet, the molecular mechanisms that control lymphatic vessel maturation remain largely unknown.


OBJECTIVE
We analyzed the gene expression profiles of ex vivo isolated lymphatic endothelial cells to identify novel lymphatic vessel expressed genes and we investigated the role of semaphorin 3A (Sema3A) and neuropilin-1 (Nrp-1) in lymphatic vessel maturation and function.


RESULTS
Lymphatic and blood vascular endothelial cells from mouse intestine were isolated using fluorescence-activated cell sorting, and transcriptional profiling was performed. We found that the axonal guidance molecules Sema3A and Sema3D were highly expressed by lymphatic vessels. Importantly, we found that the semaphorin receptor Nrp-1 is expressed on the perivascular cells of the collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1 but not with an antibody that blocks VEGF-A binding to Nrp-1 resulted in a complex phenotype of impaired lymphatic vessel function, enhanced perivascular cell coverage, and abnormal lymphatic vessel and valve morphology.


CONCLUSIONS
Together, these results reveal an unanticipated role of Sema3A-Nrp-1 signaling in the maturation of the lymphatic vascular network likely via regulating the perivascular cell coverage of the vessels thus affecting lymphatic vessel function and lymphatic valve development.
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Switzerland.
Giorgia
G
Jurisic
Hélène
H
Maby-El Hajjami
Sinem
S
Karaman
Alexandra M
AM
Ochsenbein
Annamari
A
Alitalo
Shoib S
SS
Siddiqui
Carlos
C
Ochoa Pereira
Tatiana V
TV
Petrova
Michael
M
Detmar
D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D019070:Cell Lineage; D002465:Cell Movement; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005865:Gestational Age; D006801:Humans; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000378:metabolism; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D057134:Antibodies, Neutralizing; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1