Impairment of Vascular Function in a Mouse Model of Neurofibromatosis Type 1

Abstract

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder, characterized by multiple café‐au‐lait spots, iris harmartomas, multiple nerve sheath tumors. Patients also present with heart and cerebrovascular disease, ischemia, or aneurysm. Though vasculopathy is well documented in NF1 patients, the pathophysiology is poorly understood. The objective of this study was to investigate the function and structural integrity of the thoracic aorta in a well‐established mouse model of NF1 (6‐month old). We observed a significant increase in contraction in response to depolarization of vascular smooth muscle and endothelial cells in Nf1+/‐ mice, but diminished contraction in response to phenylephrine. Interestingly, endothelium‐dependent relaxation was significantly higher in Nf1+/‐ mice, which was completely inhibited by the nitric oxide synthase (NOS) inhibitor, suggesting the relaxation results from nitric oxide (NO) production. Consistent with increased NO production, protein expression of endothelial NOS (eNOS), phospho‐eNOS, and the phospho‐Akt were increased in Nf1+/‐ aorta. Histological examination revealed that alteration in aortic function is also associated with elastin fiber disorganization within the aortic wall. This study, for the first time, underscores the pathological events underlying vascular complications in NF1, shedding light on potential new therapeutic targets to address vascular dysfunctions in NF1 patients. The presented study was funded by the Children's Tumor Foundation and the Canadian Institutes of Health Research.