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- Title
Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.
- Authors
Lasater, Elisabeth A.; Fang Li; Bessler, Waylan K.; Estes, Myka L.; Vemula, Sasidhar; Hingtgen, Cynthia M.; Dinauer, Mary C.; Kapur, Reuben; Conway, Simon J.; Ingram Jr., David A.; Li, Fang; Ingram, David A Jr
- 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.
- Subjects
VASCULAR diseases; NEUROFIBROMATOSIS; TUMOR suppressor genes; BONE marrow cells; HEMATOPOIETIC stem cells; LABORATORY mice; CELL metabolism; ANIMAL experimentation; BONE marrow; CELLS; COMPARATIVE studies; EPITHELIAL cells; HEMATOPOIETIC stem cell transplantation; RESEARCH methodology; MEDICAL cooperation; MICE; PROTEINS; RESEARCH; RESEARCH funding; SMOOTH muscle; VASCULITIS; EVALUATION research; NEUROFIBROMATOSIS 1
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 3, p859
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI41443