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UBC Theses and Dissertations

Vascular function in Neurofibromatosis 1 Jett, Kimberly Ann


Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of 1/3000. NF1 is characterized by multiple café-au-lait spots, iris hamartomas, and multiple nerve sheath tumors. Patients may also present with heart disease, cerebrovascular disease, ischemia, or aneurysm. Though well documented, vascular disease in NF1 patients remains poorly understood. Previous in vitro studies suggest that endothelial and vascular smooth muscle function is altered in Nf1+/- mice; however, it is unknown how these alterations affect vascular function in vivo. Haploinsufficiency for neurofibromin, the protein affected in patients with NF1, results in prolonged Ras hyperactivation. We hypothesized that this may result in vascular endothelial dysfunction and impaired cardiac function. To study this hypothesis we examined vascular function in Nf1+/- and control mice using wire myography. Isometric force measurements in thoracic and abdominal aorta at 6-months of age were similar, with Nf1+/- mice demonstrating altered smooth muscle function, enhanced relaxation, and upregulation of the PI3K/Akt/eNOS pathway. To determine if the alterations observed at 6 months of age remain stable or progress to a more dysfunctional state, we examined the abdominal aorta in older mice. Interestingly, we observed increased contraction and reduced relaxation in 9-to-12 month old Nf1+/-mice compared to control littermates, indicative of endothelial dysfunction and progression to a more dysfunctional state. Vascular dysfunction is likely to impact cardiac performance, and Ras hyperactivation has also been linked to cardiac dysfunction. We, therefore, used 2-dimensional echocardiography with color Doppler to measure cardiac function in Nf1+/- and control littermates. We found that Nf1+/- mice have increased left ventricular wall thickness and reduced cardiac contractility. We also observed alterations in cardiomyocyte organization in Nf1+/- animals. The results presented in this thesis support the hypothesis that neurofibromin haploinsufficiency in Nf1+/- mice results in vascular endothelial and cardiac dysfunction. Whether these findings extend to humans with NF1, who have the same genetic defect, is unknown, but if so, our observations may have important clinical implications. The role of neurofibromin in other kinds of vascular disease needs to be studied, and the possibility that neurofibromin may provide a novel therapeutic target should be explored.  

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