Fibromuscular Dysplasia (FMD) is a disease affecting the walls of medium-sized arteries throughout the body. It is defined by abnormal cell growth in the arterial wall, leading to narrowing, blockage, or bulging of the vessel. FMD is categorized as non-atherosclerotic and non-inflammatory, meaning it is not caused by the buildup of fatty plaque or systemic inflammation. Though the condition can lead to complications like high blood pressure, stroke, and aneurysm, the precise cause of FMD remains unknown. Current research points to a complex interplay of genetic susceptibility and environmental or hormonal influences that combine to trigger the disease process.
Understanding Fibromuscular Dysplasia
FMD is fundamentally a structural abnormality within the artery walls that compromises their strength and flexibility. Arteries are typically composed of three distinct layers: the inner intima, the middle media, and the outer adventitia. In FMD, the cells within one or more of these layers grow abnormally, replacing the vessel’s normally strong, flexible cells with weaker, more fibrous tissue. This defective growth causes the artery to develop irregular shapes, which impedes normal blood flow.
The most common manifestation of this abnormal growth is multifocal FMD, described as the “string of beads” sign. This distinctive appearance is caused by alternating areas of narrowed artery (stenosis) and small, balloon-like dilations (aneurysms) visible on imaging. While FMD can affect nearly any artery, it is most frequently discovered in the renal arteries, which supply the kidneys, and the carotid arteries, which carry blood to the brain. The location of the affected arteries determines the specific health consequences, such as hypertension from renal artery involvement or stroke risk from carotid artery involvement.
Genetic and Inherited Predispositions
Genetic makeup can create a biological vulnerability to developing FMD. Familial aggregation has been observed, with approximately 7% to 10% of FMD patients reporting a family history of the condition in a first or second-degree relative. This clustering points toward an inherited component, although the pattern of inheritance is complex and not a simple Mendelian trait. The genetic risk for FMD is likely conferred by multiple genes rather than a single dominant mutation.
A specific region on chromosome 6 containing the PHACTR1 gene has been identified as the first major genetic susceptibility locus for FMD. A common variant within this region is associated with an increased risk of developing the disorder by about 40%. This gene is involved in the function of both endothelial and smooth muscle cells, which form the lining and muscle layers of the arteries. The same genetic locus has also been linked to an increased risk for cervical artery dissection and migraine, conditions that frequently co-occur with FMD. This overlap suggests a shared underlying defect in the structural integrity of the arterial wall.
Hormonal and Environmental Triggers
The demographic profile of FMD points to a hormonal influence, as the disease predominantly affects women. Approximately nine out of ten FMD patients are female, and the condition is most often diagnosed between the ages of 25 and 50. This pattern has led researchers to investigate the role of sex hormones, particularly estrogen, as a potential trigger or accelerator. Though a direct cause-and-effect relationship remains difficult to prove, the association with women of childbearing age suggests that fluctuations in endogenous or exogenous hormones may play a role.
The use of exogenous hormones, such as oral contraceptives, has been investigated as a possible external factor interacting with genetic predisposition. Environmental factors are also implicated in the onset and progression of the disease. Cigarette smoking is a well-established risk factor for FMD, especially the multifocal type, and for spontaneous arterial dissections. Smoking introduces compounds that disrupt the vascular system and alter endocrine function in women, potentially exacerbating hormonal sensitivity or genetic vulnerability.
Mechanical stress on the arteries is another proposed external trigger for FMD lesions. Repeated trauma or unusual physical strain on the vessel wall, such as excessive movement or stretching, could initiate abnormal cell growth in susceptible individuals. The frequent involvement of the renal arteries, which are subject to high blood flow and repetitive movement, supports the mechanical stress hypothesis. Therefore, factors like high blood pressure, which increases sheer stress on the artery walls, may accelerate the development of FMD lesions.
Why FMD is Considered Multifactorial
Scientific consensus views FMD not as a disease with a single origin, but as a condition resulting from the interaction of multiple factors. The disease process requires an underlying genetic vulnerability that predisposes the arterial wall to abnormal development. This inherent weakness then needs an external trigger—such as hormonal shifts, toxins like those in cigarette smoke, or sustained mechanical stress—to activate the pathological cell growth.
The combination of intrinsic and extrinsic elements is required for FMD to manifest. The genetic component creates the susceptible environment, while the hormonal or environmental factor provides the necessary stimulus to initiate vascular changes. Ongoing research focuses on isolating the specific molecular pathways where these different factors intersect, aiming to better understand how a genetic risk factor like the PHACTR1 variant is affected by external conditions like smoking or estrogen levels.