Redefining Fibromuscular Dysplasia of the Arteries as a TGF- Pathway Disorder. R. Morissette1, S. Ganesh2, B. Griswold1, L. Sloper1, N. McDonnell1 1) National Institute on Aging, National Institutes of Health, Baltimore, MD; 2) Division of Cardiovascular Medicine, University of Michigan Health System, Ann Arbor, MI.

   Fibromuscular dysplasia (FMD) is a disorder involving stenosis, aneurysms, and dissections of predominantly renal and carotid arteries. Other medium sized arteries of the abdomen, intracranial vessels, and coronary arteries may also be involved. The histopathology observed is aberrant extracellular matrix deposition in the arterial wall. The disorder preferentially becomes evident in women in their fourth through sixth decade. Autosomal dominant inheritance with reduced penetrance has been suggested. Although FMD-type histopathology can be seen in a number of genetic disorders, no underlying gene mutation has been identified in the vast majority of patients who have a diagnosis of primary FMD. Clinical examination of FMD subjects from NIA protocol 2003-086 (a screening protocol for hereditary disorders of connective tissue) revealed a high prevalence of joint laxity (as defined by a Beighton score > 5), scoliosis, low bone density, and other stigmata of hereditary connective tissue dysplasias such as pes planus, pectus deformities, and dolicocephaly. Family histories were notable for increased incidence of thoracic and abdominal aneurysms in first-degree male relatives. These clinical findings as well as the extracellular matrix pathology led to the hypothesis that derangement of the TGF- pathway may play a role in the pathogenesis of FMD. To study the pathway, skin biopsy specimens were obtained from 18 FMD patients and fibroblast lines were established. Secretion of TGF-1 and TGF-2 from the FMD fibroblasts was found to be elevated compared to matched controls (p=0.0008 and p<0.0001, respectively) by ELISA. Interestingly, secreted TGF-3 was not significantly different (p>0.05), suggesting biomarker specificity in FMD pathogenesis. FMD patients also had elevated circulating TGF-2 in plasma relative to matched controls (p=0.005). Studies are underway to explore the role of TGF- signaling and other candidate pathways in FMD, as well as formulation and investigation of alternative hypotheses to explain the observed elevation of circulating and secreted TGF-1 and TGF-2.

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