Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratoge...

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Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 106; no. 21; pp. 8573 - 8578
Main Authors Therapontos, Christina, Erskine, Lynda, Gardner, Erin R, Figg, William D, Vargesson, Neil
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.05.2009
National Acad Sciences
Subjects
Angiogenesis
Animals
Apoptosis
Biological Sciences
Birth defects
Blood vessels
Cardiovascular system
Cell death
Cell growth
Cell Proliferation
Cells, Cultured
Cellular biology
Chick Embryo
Cultured cells
Cytoskeleton - drug effects
Drugs
Embryos
Endothelial cells
Gene expression
Human umbilical vein endothelial cells
Humans
Immatures
Inflammation Mediators - metabolism
Limb Deformities, Congenital - chemically induced
Limb Deformities, Congenital - embryology
Limb Deformities, Congenital - metabolism
Limb Deformities, Congenital - pathology
Neovascularization, Physiologic
Pseudopodia - drug effects
Signal Transduction
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Time Factors
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Summary:Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.
Bibliography:Author contributions: N.V. designed research; C.T., E.R.G., and N.V. performed research; W.D.F. contributed new reagents/analytic tools; C.T., L.E., E.R.G., W.D.F., and N.V. analyzed data; and L.E. and N.V. wrote the paper.
Edited by Clifford J. Tabin, Harvard Medical School, Boston, MA, and approved April 2, 2009
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0901505106