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

Xin Geng, Boksik Cha, Md Riaj Mahamud, Kim Chew Lim, Robert Silasi-Mansat, Mohammad K.M. Uddin, Naoyuki Miura, Lijun Xia, Alexander M. Simon, James Douglas Engel, Hong Chen, Florea Lupu, R. Sathish Srinivasan

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)218-233
Number of pages16
JournalDevelopmental biology
Issue number1
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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