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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

ABSTRACT: Fibromuscular dysplasia (FMD) is poorly understood but relatively common vascular disease affecting 3-5% of adult females. 1-3 The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm which can lead to hypertension, stroke, heart attack and even death. 3-7 While a limited number of gene variants have been associated with FMD,8-12 there are no animal models and few insights as to why this disease occurs. 3,13 By integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE-FMD study, we inferred 18 gene co-expression networks, of which four were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this gene co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation/aneurysm; a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. Using linkage disequilibrium score regression to determine genetic contribution to disease, 14-16 we found that this supernetwork accounts for 45.4% of FMD heritability (H2 ). These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue to address this challenging disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE242708 | GEO | 2024/04/25

REPOSITORIES: GEO

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Project description:While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cell (vSMC) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3-deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3-/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3-/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3-/- . MRI and behavioral assessments were performed in the Notch3-/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.

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Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia in Females: the DEFINE-FMD study

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