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Dissecting Neurofibromatosis Type 1 Related Vasculopathy

By Elisabeth A. Lasater

Abstract

Indiana University-Purdue University Indianapolis (IUPUI)Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the tumor suppressor gene NF1. NF1 encodes the protein neurofibromin, which functions to negatively regulate p21Ras signaling. NF1 has a wide range of clinical manifestations, including vascular disease, which is characterized by neointima formation and subsequent vessel occlusion. Despite numerous clinical observations of NF1 vasculopathy, the pathogenesis of vascular lesion formation remains unclear. To determine the consequence of Nf1 haploinsufficiency in vascular disease, we generated an in vivo model for dissecting vascular lesion formation. In response to mechanical arterial injury, Nf1+/- mice have significantly enhanced neointima formation characterized by an accumulation of vascular smooth muscle cells (VSMCs) and excessive cellular proliferation and Ras activation. Further, using the pharmacological antagonist, imatinib mesylate, we identified that neointima formation in Nf1+/- mice was directly dependent on Ras signaling through either the platelet derived growth factor β receptor (PDGF-βR) and/or the C-kit receptor activation. These observations identify a molecular mechanism of neointima formation given that our group has previously demonstrated that Nf1+/- VSMCs have hyperactive Ras signaling through PDGF-βR activation and Nf1+/- bone marrow derived cells (BMDCs) have increased recruitment and survival in response to C-kit activation compared to WT controls. In order to dissect the cellular contribution to neointima formation, we utilized cre/lox technology and adoptive hematopoietic stem cell transfer techniques to genetically delete one allele of Nf1 in endothelial cells, VSMCs or BMDCs individually to test which cell lineage is predominant in NF1 vasculopathy. Surprisingly, in response to carotid artery injury, heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation. Specifically, Nf1 haploinsufficiency in BMDCs resulted in an infiltration of macrophages into the neointima, providing evidence of “vascular inflammation” as factor in NF1 vasculopathy. Further, we demonstrate for the first time that NF1 patients have evidence of chronic inflammation determined by increased concentrations of circulating monocytes and pro-inflammatory cytokines. In sum, we 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

Topics: NF1 Cardiovascular Murine, Neurofibromatosis, Blood-vessels -- Diseases
Year: 2010
OAI identifier: oai:scholarworks.iupui.edu:1805/2064
Provided by: IUPUIScholarWorks

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