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Circ Res. 2012 Aug 3;111(4):437-45. doi: 10.1161/CIRCRESAHA.112.269316. Epub 2012 Jun 21.

Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation.

Author information

1
CIRB Collège de France/CNRS UMR 7241/INSERM U1050, Paris, France.

Abstract

RATIONALE:

The lymphatic vasculature plays a major role in fluid homeostasis, absorption of dietary lipids, and immune surveillance. Fluid transport depends on the presence of intraluminal valves within lymphatic collectors. Defective formation of lymphatic valves leads to lymphedema, a progressive and debilitating condition for which curative treatments are currently unavailable. How lymphatic valve formation is regulated remains largely unknown.

OBJECTIVE:

We investigated if the repulsive axon guidance molecule Semaphorin3A (Sema3A) plays a role in lymphatic valve formation.

METHODS AND RESULTS:

We show that Sema3A mRNA is expressed in lymphatic vessels and that Sema3A protein binds to lymphatic valves expressing the Neuropilin-1 (Nrp1) and PlexinA1 receptors. Using mouse knockout models, we show that Sema3A is selectively required for lymphatic valve formation, via interaction with Nrp1 and PlexinA1. Sema3a(-/-) mice exhibit defects in lymphatic valve formation, which are not due to abnormal lymphatic patterning or sprouting, and mice carrying a mutation in the Sema3A binding site of Nrp1, or deficient for Plxna1, develop lymphatic valve defects similar to those seen in Sema3a(-/-) mice.

CONCLUSIONS:

Our data demonstrate an essential direct function of Sema3A-Nrp1-PlexinA1 signaling in lymphatic valve formation.

PMID:
22723296
PMCID:
PMC3861899
DOI:
10.1161/CIRCRESAHA.112.269316
[Indexed for MEDLINE]
Free PMC Article

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