Characterizing Myeloid Cell Activation in NF1 Vasculopathy

Persons with neurofibromatosis type 1 (NF1) are predisposed to premature and debilitating cardiovascular disease. Cardiovascular disease commonly presents as hypertension, arterial stenosis, and aortic aneurysm formation in young adults with NF1 and places them at significant risk for sudden death due to stroke or aneurysm rupture. We have developed mouse models of NF1 arterial stenosis and aortic aneurysm to aid our understanding of how these manifestations of NF1 develop. Mice with inherited mutations in one copy of the Nf1 gene, similar to inherited mutations in humans, are predisposed to arterial stenosis and aortic aneurysm formation. We previously showed that mutation of the Nf1 gene in circulating white blood cells, specifically monocytes and neutrophils, is critical for arterial stenosis and aortic aneurysm formation in mice. Examination of these arterial lesions shows a substantial increase in infiltrating macrophages to the vessel wall. We isolated macrophages from Nf1 mutant mice to examine the role of neurofibromin in regulating macrophage function. Compared to wild mice, macrophages isolated from Nf1 mutant mice show increased mobilization to sites of inflammation and secrete growth factors that are important in multiple forms of cardiovascular disease. Additionally, Nf1 macrophages produce large amounts of reactive oxygen species, which exhibit multiple effects in cardiovascular disease development. Therefore, we hypothesize that macrophages from Nf1 mutant mice are preferentially mobilized from the bone marrow to sites of vascular injury and produce growth factors and reactive oxygen species to induce cardiovascular disease. A close examination of macrophage function in Nf1 mutant mice will provide valuable insight into why NF1 patients develop cardiovascular disease and may uncover why some NF1 patients develop arterial stenosis while others are at risk for aneurysm formation. An understanding of how these lesions form will help clinicians to identify 'at-risk' patients prior to cardiovascular collapse and will inform targeted therapies for the treatment and/or prevention of cardiovascular disease in NF1 patients. Findings in the proposed experiments are directly translational to NF1 patients with cardiovascular disease and will serve as the foundation for new therapeutic trials in these patients. As macrophages are important cells in the development of several manifestations of NF1, our studies may shed light on how and why NF1 patients develop neurofibromas, malignant peripheral nerve sheath tumors, and leukemia.