Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation
- Christina Therapontosa,b,
- Lynda Erskineb,
- Erin R. Gardnerc,
- William D. Figgd and
- Neil Vargessona,b,1
- aNational Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, United Kingdom;
- bSchool of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom;
- cClinical Pharmacology Program, SAIC-Frederick, Inc., National Cancer Institute, Frederick, MD 21702; and
- dMolecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
-
Edited by Clifford J. Tabin, Harvard Medical School, Boston, MA, and approved April 2, 2009 (received for review February 10, 2009)
Abstract
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.
Footnotes
- 1To whom correspondence should be addressed. E-mail: n.vargesson{at}abdn.ac.uk
-
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.
-
The authors declare no conflict of interest.
-
This article is a PNAS Direct Submission.
