Dysfunctions of the Abdominal Aorta and Renal Arteries in a Mouse Model of Neurofibromatosis Type 1

Abstract

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder presented with multiple café‐au‐lait spots, Lisch nodules,multiple nerve sheath tumors, and cardiovascular complications such as ischemia or aneurysm. Multiple vessels are affected in NF1 patients, but the abdominal aorta (AA) and renal arteries (RA) are most commonly reported, even though, the pathogenesis is not well understood. In this study, we examined functions of the AA and RA in a mouse model of NF1. We report a decrease in contraction and an increase in relaxation of smooth muscle cells (SMCs) in both the AA and RA at the age of 6 months. The nitric oxide synthase inhibitor (L‐NAME) completely blocked SMCs relaxation, indicating that the alterations resulted from enhanced nitric oxide (NO) production. The constitutional production of NO may reduce the availability of cofactors required for endothelial NOS to function. To determine if the increased production of NO had caused further dysfunction over time, we examined the AA in 9‐12 month old mice. Interestingly, we observed increased contraction and reduced relaxation in 9‐12 month old Nf1+/‐mice compared to controls, which may be indicative of a further decrease in NO bio‐availability. Taken together, our data demonstrates that underlying changes in SMCs and the endothelium contribute to vascular complications in NF1, providing new insights on potential future therapeutic approaches to address vascular complications in these patients. This study was funded by the British Columbia Neurofibromatosis Foundation and the Children's Tumor Foundation.