title: Pulmonary lymphangiectasia resulting from vascular endothelial growth factor-C overexpression during a critical period.
abstract: BACKGROUND
  Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions they can grow as enlarged, dilated sacs that result in the potentially lethal condition of pulmonary lymphangiectasia.
  
  
  OBJECTIVE
  We sought to determine whether overexpression of the lymphangiogenic growth factor (vascular endothelial growth factor-C [VEGF-C]) can promote lymphatic growth and maturation in the respiratory tract. Unexpectedly, perinatal overexpression of VEGF-C in the respiratory epithelium led to a condition resembling human pulmonary lymphangiectasia, a life-threatening disorder of the newborn characterized by respiratory distress and the presence of widely dilated lymphatics.
  
  
  RESULTS
  Administration of doxycycline to Clara cell secretory protein-reverse tetracycline-controlled transactivator/tetracycline operator-VEGF-C double-transgenic mice during a critical period from embryonic day 15.5 to postnatal day 14 was accompanied by respiratory distress, chylothorax, pulmonary lymphangiectasia, and high mortality. Enlarged sac-like lymphatics were abundant near major airways, pulmonary vessels, and visceral pleura. Side-by-side comparison revealed morphological features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age postnatal day 14 and did not develop after postnatal day 35. Mechanistic studies revealed that VEGF recptor (VEGFR)-3 alone drove lymphatic growth in adult mice, but both VEGFR-2 and VEGFR-3 were required for the development of lymphangiectasia in neonates. VEGFR-2/VEGFR-3 heterodimers were more abundant in the dilated lymphatics, consistent with the involvement of both receptors. Despite the dependence of lymphangiectasia on VEGFR-2 and VEGFR-3, the condition was not reversed by blocking both receptors together or by withdrawing VEGF-C.
  
  
  CONCLUSIONS
  The findings indicate that VEGF-C overexpression can induce pulmonary lymphangiectasia during a critical period in perinatal development.
authors.affiliation: From the Department of Anatomy, Cardiovascular Research Institute, Comprehensive Cancer Center, University of California, San Francisco (L.-C.Y., P.B., D.M.M.); Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden (C.T., L.C.-W.); Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki and University of Helsinki, Helsinki, Finland (D.T., A.A., K.A.); Department of Pathology, Boston Children's Hospital, Harvard University, MA (S.O.V.), and Department of Cell Biology, ImClone Systems, Eli Lilly and Company, New York (B.P.).
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Yao
authors.forename: Chiara
authors.initials: C
authors.lastname: Testini
authors.forename: Denis
authors.initials: D
authors.lastname: Tvorogov
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Sara O
authors.initials: SO
authors.lastname: Vargas
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007223:Infant; D008171:Lung Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008200:Lymphangiectasis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011247:Pregnancy; D011654:Pulmonary Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014132:Trachea / Q000378:metabolism / Q000473:pathology; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: C556390:Scgb1a1 protein, mouse; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D014598:Uteroglobin; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGFR-2; VEGFR-3; chylothorax; lung; lymphangiogenesis; lymphangiomatosis, pulmonary; lymphatic vessels; pulmonary edema