Format

Send to

Choose Destination
Sci Signal. 2014 Oct 14;7(347):ra97. doi: 10.1126/scisignal.2005413.

Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function.

Author information

1
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma, OK 73104, USA.
2
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA.
3
Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
4
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA.
5
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma, OK 73104, USA. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA.
6
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK 73126, USA.
7
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma, OK 73104, USA. hong-chen@omrf.org.

Abstract

Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin-deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation.

PMID:
25314967
PMCID:
PMC4226761
DOI:
10.1126/scisignal.2005413
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center