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Human Molecular Genetics Advance Access published online on April 28, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn134
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nf1 +/- Mice Have Increased Neointima Formation Via Hyperactivation of a Gleevec Sensitive Molecular Pathway

Elisabeth A. Lasater1,2,3, Waylan K. Bessler1,2, Laura E. Mead1,2, Whitney E. Horn1,2, D. Wade Clapp1,2,4, Simon J. Conway1,2,3, David A. Ingram1,2,3,* and Fang Li1,2

1 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202 2 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 4 Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202

* Corresponding Author: David A. Ingram M.D. Indiana University School of Medicine Herman B Wells Center for Pediatric Research 1044 W. Walnut St R4/470 Indianapolis, IN 46202 (317) 278-8245 (317) 274-8679 (Fax) E-mail: dingram{at}iupui.edu

Received February 20, 2008; Revised April 21, 2008; Accepted April 21, 2008

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the NF1 tumor suppressor gene. Neurofibromin is encoded by NF1 and functions as a negative regulator of Ras activity. Somatic mutations in the residual normal NF1 allele within cancers of NF1 patients is consistent with NF1 functioning as a tumor-suppressor. However, the prevalent nonmalignant manifestations of NF1, including learning and bone disorders emphasize the importance of dissecting the cellular and biochemical effects of NF1 haploinsufficiency in multiple cell lineages. One of the least studied complications of NF1 involves cardiovascular disorders, including arterial occlusions that result in cerebral and visceral infarcts. NF1 vasculopathy is characterized by vascular smooth muscle cell (VSMC) accumulation in the intima area of vessels resulting in lumen occlusion. We recently showed that Nf1 haploinsufficiency increases VSMC proliferation and migration via hyperactivation of the Ras-Erk pathway, which is a signaling axis directly linked to neointima formation in diverse animal models of vasculopathy. Given this observation, we tested whether heterozygosity of Nf1 would lead to vasoocclusive disease in genetically engineered mice in vivo. Strikingly, Nf1+/- mice have increased neointima formation, excessive vessel wall cell proliferation and Erk activation after vascular injury in vivo. Further, this effect is directly dependent on a Gleevec sensitive molecular pathway. Therefore, these studies establish an Nf1 model of vasculopathy, which mirrors features of human NF1 vasoocclusive disease, identifies a potential therapeutic target, and provides a platform to further dissect the effect of Nf1 haploinsufficiency in cardiovascular disease.


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