1. Integrative gene regulatory network analysis discloses key driver genes of fibromuscular dysplasia.
- Author
-
d'Escamard V, Kadian-Dodov D, Ma L, Lu S, King A, Xu Y, Peng S, V Gangula B, Zhou Y, Thomas A, Michelis KC, Bander E, Bouchareb R, Georges A, Nomura-Kitabayashi A, Wiener RJ, Costa KD, Chepurko E, Chepurko V, Fava M, Barwari T, Anyanwu A, Filsoufi F, Florman S, Bouatia-Naji N, Schmidt LE, Mayr M, Katz MG, Hao K, Weiser-Evans MCM, Björkegren JLM, Olin JW, and Kovacic JC
- Subjects
- Humans, Female, Animals, Case-Control Studies, Genetic Predisposition to Disease, Cells, Cultured, Male, Middle Aged, Disease Models, Animal, Adult, Phenotype, Mice, Inbred C57BL, Gene Expression Regulation, Mice, Fibromuscular Dysplasia genetics, Fibromuscular Dysplasia pathology, Gene Regulatory Networks, Fibroblasts metabolism, Fibroblasts pathology, Mice, Knockout
- Abstract
Fibromuscular dysplasia (FMD) is a poorly understood disease affecting 3-5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm, which can lead to hypertension, stroke, myocardial infarction and even death. Currently, there are no animal models for FMD and few insights as to its pathobiology. In this study, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 patients with FMD and 71 matched healthy controls, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation, a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue for this challenging disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF