title: Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.
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.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Geng
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Boksik
authors.initials: B
authors.lastname: Cha
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Md Riaj
authors.initials: MR
authors.lastname: Mahamud
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Mohammad K M
authors.initials: MKM
authors.lastname: Uddin
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Simon
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.affiliation: 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.
authors.forename: R Sathish
authors.initials: RS
authors.lastname: Srinivasan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000648:ultrastructure; D042601:Lymphatic Vessels / Q000196:embryology* / Q000648:ultrastructure; D008209:Lymphedema / Q000196:embryology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D019683:Penetrance; D010641:Phenotype; D055422:Venous Valves / Q000196:embryology* / Q000648:ultrastructure