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journal contribution
posted on 2019-03-06, 14:07 authored by Brian Stansfield

Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease.

Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin,

leads to accelerated p21Ras activity and phosphorylation of multiple downstream kinases, including Erk

and Akt. Nf1 heterozygous (Nf1./-) mice develop a robust neointima that mimics human disease.

Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells

alone are sufficient to reproduce the enhanced neointima observed in Nf1./- mice. Though the molecular

mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of

reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound

mutant and lineage-restricted mice to demonstrate that Nf1./- macrophages produce excessive ROS,

which enhance Nf1./- smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific

NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1./- mice. Finally,

mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator

of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that

excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing

novels therapies and interventions.


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