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Dev Biol. 2016 Jan 1;409(1):218-233. doi: 10.1016/j.ydbio.2015.10.022. Epub 2015 Nov 2.

Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.

Author information

1
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
2
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
3
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
4
Department of Physiology, University of Arizona, Tucson, AZ, USA.
5
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: sathish-srinivasan@omrf.org.

Abstract

Lymph is returned to the blood circulation exclusively via four lymphovenous valves (LVVs). Despite their vital importance, the architecture and development of LVVs is poorly understood. We analyzed the formation of LVVs at the molecular and ultrastructural levels during mouse embryogenesis and identified three critical steps. First, LVV-forming endothelial cells (LVV-ECs) differentiate from PROX1(+) progenitors and delaminate from the luminal side of the veins. Second, LVV-ECs aggregate, align perpendicular to the direction of lymph flow and establish lympho-venous connections. Finally, LVVs mature with the recruitment of mural cells. LVV morphogenesis is disrupted in four different mouse models of primary lymphedema and the severity of LVV defects correlate with that of lymphedema. In summary, we have provided the first and the most comprehensive analysis of LVV development. Furthermore, our work suggests that aberrant LVVs contribute to lymphedema.

PMID:
26542011
PMCID:
PMC4688075
DOI:
10.1016/j.ydbio.2015.10.022
[Indexed for MEDLINE]
Free PMC Article

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