Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Elisabeth A. Lasater, Fang Li, Waylan K. Bessler, Myka L. Estes, Sasidhar Vemula, Cynthia M. Hingtgen, Mary C. Dinauer, Reuben Kapur, Simon Conway, David Ingram

Research output: Contribution to journalArticle

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Abstract

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1+/- mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.

Original languageEnglish
Pages (from-to)859-870
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number3
DOIs
StatePublished - Mar 1 2010

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Neurofibromin 1
Neurofibromatosis 1
Blood Vessels
Inflammation
Neointima
Vascular Diseases
Bone Marrow Cells
Vascular System Injuries
Hematopoietic Stem Cell Transplantation
Cell Lineage
Tumor Suppressor Genes
Vascular Smooth Muscle
Smooth Muscle Myocytes
Homeostasis
Endothelial Cells
Alleles
Cytokines
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. / Lasater, Elisabeth A.; Li, Fang; Bessler, Waylan K.; Estes, Myka L.; Vemula, Sasidhar; Hingtgen, Cynthia M.; Dinauer, Mary C.; Kapur, Reuben; Conway, Simon; Ingram, David.

In: Journal of Clinical Investigation, Vol. 120, No. 3, 01.03.2010, p. 859-870.

Research output: Contribution to journalArticle

Lasater, Elisabeth A. ; Li, Fang ; Bessler, Waylan K. ; Estes, Myka L. ; Vemula, Sasidhar ; Hingtgen, Cynthia M. ; Dinauer, Mary C. ; Kapur, Reuben ; Conway, Simon ; Ingram, David. / Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 3. pp. 859-870.
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