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.