title: Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.
abstract: Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA; nazli.mcdonnell@gmail.com sganesh@umich.edu.
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA; nazli.mcdonnell@gmail.com sganesh@umich.edu.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Johns Hopkins Bayview Proteomics Center, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA;
authors.forename: Florian
authors.initials: F
authors.lastname: Schoenhoff
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Griswold
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Lan
authors.initials: L
authors.lastname: Tong
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Min-Lee
authors.initials: ML
authors.lastname: Yang
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Kristina
authors.initials: K
authors.lastname: Hunker
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Leslie
authors.initials: L
authors.lastname: Sloper
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Shinie
authors.initials: S
authors.lastname: Kuo
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Rafi
authors.initials: R
authors.lastname: Raza
authors.affiliation: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas, USA;
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: Greater Baltimore Medical Center, Towson, Maryland, USA;
authors.forename: Clair A
authors.initials: CA
authors.lastname: Francomano
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and Howard Hughes Medical Institute, Baltimore, Maryland, USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Johns Hopkins Bayview Proteomics Center, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Eyk
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA; nazli.mcdonnell@gmail.com sganesh@umich.edu.
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
mesh_terms: D000328:Adult; D000368:Aged; D001139:Arnold-Chiari Malformation / Q000150:complications; D015415:Biomarkers / Q000097:blood; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000209:etiology; D016022:Case-Control Studies; D002453:Cell Cycle; D002460:Cell Line; D003238:Connective Tissue / Q000473:pathology; D020405:Dermis / Q000473:pathology; D004108:Dilatation, Pathologic; D004388:Dura Mater / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005352:Fibromuscular Dysplasia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000209:etiology; D018836:Inflammation Mediators / Q000097:blood; D007593:Joint Instability / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012077:Renal Artery / Q000473:pathology; D016037:Single-Blind Method; D013131:Spine / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000097:blood / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
keywords: FMD; TGF-β; biomarker; human genetics; pathway aneurysm
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