The complex genetic basis of fibromuscular dysplasia, a systemic arteriopathy associated with multiple forms of cardiovascular disease

Abstract

Artery stenosis is a common cause of hypertension and stroke and can be due to atherosclerosis accumulation in the majority of cases and in a small fraction of patients to arterial fibromuscular dysplasia (FMD). Artery stenosis due to atherosclerosis is widely studied with known risk factors (e.g. increasing age, male gender, and dyslipidemia) to influence its etiology, including genetic factors. However, the causes of noninflammatory and nonatherosclerotic stenosis in FMD are less understood. FMD occurs predominantly in early middle-age women, a fraction of the population where cardiovascular risk is different and understudied. FMD arteriopathies are often diagnosed in the context of hypertension and stroke and co-occur mainly with spontaneous coronary artery dissection, an atypical cause of acute myocardial infarction. In this review, we provide a comprehensive overview of the recent advances in the understanding of molecular origins of FMD. Data were obtained from genetic studies using complementary methodological approaches applied to familial, syndromic, and sporadic forms of this intriguing arteriopathy. Rare variation analyses point toward mechanisms related to impaired prostacyclin signaling and defaults in fibrillar collagens. The study of common variation, mainly through a recent genome-wide association study, describes a shared genetic link with blood pressure, in addition to point at potential risk genes involved in actin cytoskeleton and intracellular calcium homeostasis supporting impaired vascular contraction as a key mechanism. We conclude this review with future strategies and approaches needed to fully understand the genetic and molecular mechanisms related to FMD.

Keywords: arteriopathy; cardiovascular disease in women; fibromuscular dysplasia; genetics.

Figure 1. Myosin heavy chain 11 (MYH11) immunostaining of renal artery from 56-year-old woman presenting FMD lesions (Courtesy from Patrick Bruneval, HEGP Pathology Department)

Figure 2. Venn diagram summarizing the genetic overlap between FMD and associated cardiovascular diseases

Figure 3. Molecular functions where FMD associated genes are suspected to act in SMCs

Arrows indicate the risk of FMD is correlated with up-regulation (green) or down-regulation (red) of gene expression. Simple cross symbolizes heterozygous and double cross homozygous missense or loss of function mutations which were reported in the genes. Interrogation marks indicate suspected biological mechanisms. Mechanisms or genes in red are also associated with arterial dissection.