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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 a poorly understood but relatively common vascular 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, heart attack and even death. While a limited number of gene variants have been associated with FMD, there are no animal models and few insights as to why this disease occurs. 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, four of which 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; 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 the genetic contribution to disease, we found that this supernetwork accounts for a significant proportion of FMD heritability (H squared). These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue to address this challenging disease.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Aorta

SUBMITTER: XIAOKE YIN

LAB HEAD: Manuel Mayr

PROVIDER: PXD051750 | Pride | 2024-05-01

REPOSITORIES: Pride

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Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype. 5 WT C57Bl/6 and 5 mice that express the Ca2+/calmodulin-dependent kinase II peptide inhibitor CaMKIIN in smooth muscle only (TG SM-CaMKIIN) were infused with 1.25 ug/kg/min Angiotensin-II by osmotic minipump for 14 days. 5 WT and 5 transgenic mice infused with normal saline served as controls. The mice were sacrificed on day 14 and the thoracic aortas isolated. RNA was isolated and pooled for the following groups: WT (wild type), C (TG SM-CaMKIIN), WT-A (WT with Angiotensin-II), C-A (TG SM-CaMKIIN + Angiotensin-II)

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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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