Intracranial Arterial Stenosis beyond Atherosclerosis: Insights fromRNF213

Abstract

Intracranial arterial stenosis is a major cause of ischemic stroke worldwide, particularly in the Asian population. Although traditionally regarded as a manifestation of atherosclerotic disease, increasing evidence suggests that non-atherosclerotic arteriopathies also contribute substantially to its pathogenesis. These conditions, including arterial dissection, inflammatory vasculopathies, and moyamoya disease, often share overlapping clinical and imaging features, thus making precise differentiation challenging in routine practice.

This phenotypic overlap highlights the heterogeneity of intracranial arterial stenosis and suggests that it may represent a spectrum of vascular disorders, rather than a single disease entity. Recent studies have highlighted the role of genetic susceptibility as a factor underlying this diversity. Among these,RNF213, originally identified as a susceptibility gene for moyamoya disease, has been implicated in a subset of intracranial arterial diseases beyond the classical diagnostic categories. These observations have led to the concept ofRNF213-related vasculopathy, which extends beyond intracranial circulation and provides a framework for understanding diverse vascular phenotypes within a broader context. In addition, a two-hit model has been proposed in which genetic susceptibility interacts with environmental and acquired factors to influence the disease onset and progression.

This narrative review summarizes the current understanding of intracranial arterial stenosis beyond the conventional atherosclerosis-centered paradigm and discusses emerging concepts integrating vascular heterogeneity, genetic susceptibility, and environmental modifiers with potential implications for disease classification and individualized therapeutic strategies.

Introduction

Intracranial arterial stenosis is a major cause of ischemic stroke worldwide and it represents a particularly important subtype in the Asian population ^{1 , 2)} . Epidemiological studies have demonstrated a marked geographical disparity, with intracranial stenosis accounting for 30–50% of ischemic strokes in East and Southeast Asia compared with 10–15% in Western populations ^{2 - 4)} . Symptomatic intracranial stenosis is associated with a substantial risk of recurrent stroke ⁵⁾ . Given its high prevalence and clinical impact, intracranial arterial stenosis remains a critical target for clinical research and therapeutic interventions.

Traditionally, intracranial arterial stenosis has been regarded primarily as a manifestation of atherosclerotic disease, and this paradigm has guided diagnostic and therapeutic strategies that focus on conventional vascular risk factors ⁶⁾ . However, this framework is increasingly recognized as being insufficient. Some patients, particularly younger individuals or those with a low burden of conventional risk factors, cannot be adequately explained by atherosclerosis alone ⁷⁾ . These observations suggest that intracranial arterial stenosis represents a heterogeneous group of vascular disorders rather than a single disease entity.

Among the potential mechanisms underlying this heterogeneity, genetic susceptibility has attracted increasing attention. RNF213, originally identified as a susceptibility gene for moyamoya disease ^{8 , 9)} , has been implicated in a subset of intracranial arterial diseases, including lesions traditionally classified as atherosclerotic lesions ¹⁰⁾ . These findings suggest that the genetic background may contribute, at least in part, to vascular vulnerability across different disease entities.

In this narrative review, we summarize the current understanding of intracranial arterial stenosis beyond the conventional atherosclerosis-centered model. We then discuss the emerging role of RNF213 and the concept of RNF213-related vasculopathy and propose a unified framework based on a two-hit hypothesis with potential implications for precision medicine.

Classical Intracranial Atherosclerotic Disease

Intracranial atherosclerotic disease has traditionally been regarded as the principal mechanism of intracranial arterial stenosis. Pathologically, it is characterized by eccentric plaque formation within the arterial wall, with variable contributions from lipid-rich necrotic components, inflammatory cell infiltration, calcification, and intraplaque hemorrhage ¹¹⁾ . These pathological features may be reflected on high-resolution vessel wall imaging as eccentric wall thickening, plaque enhancement, and, in selected cases, T1-hyperintense lesions suggestive of intraplaque hemorrhage ¹²⁾ . Histopathological correlation studies have further demonstrated that signal heterogeneity on vessel wall imaging corresponds to underlying plaque components, particularly in more advanced lesions ¹³⁾ .

From a clinical perspective, intracranial atherosclerosis is closely linked to conventional vascular risk factors, and its management has focused on antithrombotic therapy and aggressive control of hypertension, dyslipidemia, diabetes mellitus, and smoking ^{14 , 15)} . The mechanisms by which it causes ischemic stroke are diverse and include artery-to-artery embolism, perforator branch occlusion, and hemodynamic compromise.

However, not all cases of intracranial arterial stenosis can be adequately explained by atherosclerosis. This is particularly evident in younger patients and those with a low burden of conventional vascular risk factors ⁷⁾ . These limitations highlight the need to consider additional mechanisms beyond classical atherosclerosis in the pathogenesis of intracranial arterial diseases.

Spectrum of Non-Atherosclerotic ICAS

Non-atherosclerotic causes of intracranial arterial stenosis are increasingly recognized as important contributors to cerebrovascular diseases ⁷⁾ . These include a heterogeneous group of intracranial arteriopathies, such as arterial dissection, inflammatory vasculopathies, reversible cerebral vasoconstriction syndrome, and moyamoya disease.

The spectrum of non-atherosclerotic intracranial arteriopathies includes several distinct entities with unique pathophysiological mechanisms. Intracranial arterial dissection is characterized by intimal disruption of the endothelium and intramural hematoma formation, often resulting in eccentric luminal narrowing or occlusion ¹⁶⁾ . Inflammatory vasculopathies, such as primary central nervous system vasculitis, typically involve diffuse inflammatory cell infiltration and concentric wall thickening ¹⁷⁾ . In contrast, reversible cerebral vasoconstriction syndrome is primarily a functional disorder of vascular tone, characterized by transient vasoconstriction with minimal structural alterations of the vessel wall ¹⁸⁾ . Moyamoya disease is a chronic steno-occlusive arteriopathy characterized by progressive intimal thickening, vessel shrinkage, and the development of abnormal collateral networks ¹⁹⁾ .

High-resolution vessel wall imaging has facilitated the in vivo characterization of these arteriopathies by enabling direct visualization of the vessel wall ²⁰⁾ . Non-atherosclerotic arteriopathies often exhibit patterns distinct from classical atherosclerosis, such as concentric wall thickening in inflammatory conditions, intramural hematoma in arterial dissection, minimal wall changes in reversible cerebral vasoconstriction syndrome, and negative remodeling in moyamoya disease ^{20 , 21)} . However, these imaging features are not always specific to the disease.

Despite these characteristic imaging features, considerable overlap exists between intracranial arteriopathies in terms of clinical presentation and the vessel wall imaging findings. For example, inflammatory changes and wall enhancement may also be observed in atherosclerotic lesions, making differentiation from vasculitis challenging in some cases ^{12 , 20)} . Similarly, distinguishing intramural hematoma in arterial dissection from the hemorrhagic components within atherosclerotic plaques may be difficult ¹²⁾ . In East Asian populations, early stage moyamoya disease may mimic atherosclerotic or other intracranial arteriopathies, particularly when the characteristic collateral vessels are not yet evident ¹⁹⁾ .

Taken together, these observations highlight the limitations of a purely morphology-based classification and suggest that intracranial arterial stenosis may, at least in part, represent a continuum of vascular disorders with partially overlapping mechanisms. This perspective provides a rationale for incorporating additional factors, including genetic susceptibility, into the conceptual framework of intracranial arterial diseases.

RNF213 and Intracranial Arterial Disease

The recognition of substantial phenotypic overlap among intracranial arteriopathies has prompted increasing interest in the role of genetic susceptibility in intracranial arterial diseases. Among the candidate genes, RNF213 has emerged as a major susceptibility gene, initially identified in moyamoya disease through genetic studies in East Asian populations ^{8 , 9)} . Subsequent investigations have demonstrated that RNF213 variants are not restricted to moyamoya disease, but they are also associated with intracranial arterial stenosis in patients without classical moyamoya features ^{22 , 23)} .

The RNF213 p.R4810K variant has been shown to confer a substantial increase in the risk of intracranial arterial disease, particularly in East Asian populations. In a large-scale genetic study of ischemic stroke, this variant was strongly associated with large-artery atherosclerotic stroke, with an approximately 3.5-fold increased risk and an earlier age at onset ¹⁰⁾ . Furthermore, longitudinal studies have indicated that this variant is associated with the accelerated progression of intracranial arterial stenosis, including asymptomatic lesions ^{24 , 25)} . A genome-wide association study of intracranial arterial stenosis in Japanese individuals identified p.R4810K as the only variant reaching genome-wide significance with a markedly large effect size ²⁶⁾ . These findings support the notion that RNF213 contributes to disease susceptibility in a subset of intracranial arterial stenosis cases.

Beyond these associations, accumulating evidence suggests that RNF213 is linked to a broad spectrum of intracranial arteriopathies. RNF213 variants have been reported not only in atherosclerotic intracranial stenosis but also in conditions such as intracranial arterial dissection and autoimmune-associated vasculopathy. For example, an increased prevalence of the p.R4810K variant has been observed in patients with intracranial arterial dissection, suggesting its role in intrinsic vascular fragility ²⁷⁾ . In addition, associations between moyamoya disease and autoimmune conditions, particularly Graves’ disease, have long been recognized. RNF213 variant carriers have been shown to exhibit elevated thyroid autoantibody titers even in the absence of overt moyamoya disease ²⁸⁾ , and a substantial proportion of patients with autoimmune-associated quasi-moyamoya disease harbor this variant ²⁹⁾ . These observations suggest that immune-mediated mechanisms may act as disease modifiers in genetically susceptible patients.

Building on these findings, the concept of “RNF213-related vasculopathy” has been proposed to describe the spectrum of vascular phenotypes associated with RNF213 variants ¹⁰⁾ . This framework extends beyond traditional diagnostic categories and provides a unifying perspective for understanding the heterogeneity of intracranial arterial diseases.

RNF213-related Vasculopathy as a Systemic Disease

Accumulating evidence indicates that RNF213-related vasculopathy extends beyond the intracranial circulation and it should be regarded as a systemic vascular disease involving multiple arterial beds ( Fig.1 ) . While initially identified in the context of moyamoya disease, RNF213-associated vascular pathology is increasingly recognized in extracranial vascular territory.

Fig.1. Systemic spectrum of RNF213-related vasculopathy .

RNF213-related vasculopathy is associated with vascular abnormalities affecting multiple arterial beds, including the intracranial, pulmonary, coronary, and systemic arteries. These manifestations can present with varying extents of involvement, ranging from single-territory to multisystem involvement, with potential overlap between different vascular territories. This spectrum reflects the substantial phenotypic heterogeneity arising from a shared genetic background.

Evidence of systemic involvement is particularly evident in homozygous carriers of the RNF213 p.R4810K variant. Vascular abnormalities affecting multiple arterial beds have been described in these individuals, even in the absence of typical moyamoya angiographic features ³⁰⁾ . RNF213 variants have been linked to specific vascular conditions in different organ systems. In the cardiovascular system, they are associated with coronary artery abnormalities, particularly vasospastic angina, suggesting altered vascular reactivity ^{31 , 32)} . Associations with pulmonary vascular diseases, including pulmonary arterial hypertension, have also been reported ^{33 , 34)} .

Importantly, the systemic nature of RNF213-related vasculopathy is not reflected in a uniform pattern of multi-organ involvement. Instead, carriers of the same variant may develop distinct vascular phenotypes, such as intracranial, coronary, and pulmonary vascular diseases, which do not simply represent extensions of moyamoya disease.

These findings support the view that moyamoya disease represents one phenotype within a broader spectrum of RNF213-related vasculopathy. The mechanisms underlying this phenotypic diversity remain incompletely understood, but they are likely influenced by additional genetic, environmental, and acquired factors that influence disease expression.

Two-Hit Hypothesis and Clinical Implications

Accumulating experimental evidence has begun to elucidate the molecular functions of the RNF213 protein. RNF213 protein has been implicated in multiple biological processes across diverse cellular systems ( Fig.2 ) , including the endothelial function and angiogenic responses in vascular cells, as well as the roles in lipid metabolism and cell-autonomous immunity ^{35- 39)} .

Fig.2. Pleiotropic biological functions of RNF213 protein across multiple cellular systems.

RNF213 is implicated in diverse biological processes, including angiogenesis, lipid metabolism, hypoxia response, tumor suppression, and regulation of immune responses. It also plays a role in host defense against pathogens, including ubiquitin-mediated responses to bacterial components, such as lipopolysaccharides (LPS). These interconnected processes suggest that RNF213 contributes to vascular vulnerability through complex interactions across multiple cellular systems.

These observations suggest that RNF213 protein exerts pleiotropic effects across both vascular and non-vascular systems. However, no single molecular pathway accounts for the diverse vascular phenotypes associated with RNF213 variants, including variability in clinical presentation and vascular territories involved.

In this context, a “two-hit” hypothesis has been proposed, in which RNF213 variants confer an underlying vulnerability to the vascular system, while additional genetic, environmental, or acquired factors influence both disease onset and progression ¹⁹⁾ . Within this framework, these factors may modulate the timing, location, and phenotype of disease expression.

One example of this variability is the bimodal age distribution observed in moyamoya disease, with peaks in childhood and adulthood ^{19 , 40)} . Pediatric-onset disease may, in part, be associated with physiological or environmental stressors such as hypoxia or infection and reflect contributions from additional genetic factors beyond RNF213. In contrast, adult-onset disease may be more closely associated with chronic inflammatory conditions and/or conventional vascular risk factors. These differences likely represent variations in the potential modifying factors across the lifespan.

From a clinical perspective, this framework may provide a conceptual basis for a more individualized understanding of intracranial arterial disease ( Fig.3 ) . The integration of genetic susceptibility with biological and environmental modifiers could help refine risk stratification and disease classification. However, these concepts remain largely hypothetical, and further studies are required to clarify their clinical significance.

Fig.3. Conceptual framework of the two-hit hypothesis and potential modifying factors in RNF213-related vasculopathy .

RNF213 variants confer an underlying vascular vulnerability, whereas additional factors, such as hypoxia, infection, autoimmune conditions, and dyslipidemia, may act as secondary triggers influencing disease development and progression. Potential strategies to modify these factors, including perinatal management, vaccination, immunomodulatory therapies, and lipid-lowering treatments, are illustrated, although their clinical relevance remains to be established.

Conclusion

Intracranial arterial stenosis encompasses a heterogeneous spectrum of vascular disorders with diverse underlying mechanisms that extend beyond atherosclerosis alone. Although traditionally viewed through an atherosclerosis-centered framework, non-atherosclerotic arteriopathies have likely been under-recognized due to the limitations of conventional lumen-based assessments. Recent advances in high-resolution vessel wall imaging and genetic studies have provided new insights into vessel wall pathology and disease susceptibility, highlighting the increasing importance of non-atherosclerotic and genetically influenced mechanisms in intracranial arterial diseases.

Within this evolving framework, RNF213 has emerged as a key factor contributing to vascular vulnerability and phenotypic diversity, particularly in the East Asian population. The concept of RNF213-related vasculopathy and the two-hit hypothesis offer a unifying perspective that integrates genetic susceptibility with environmental and acquired modifiers of disease. Although these concepts remain to be fully validated, they provide a basis for rethinking disease classification and moving toward a more mechanism-based and individualized approach to intracranial arterial disease.

Acknowledgement

The author used ChatGPT (OpenAI, GPT-5.3) to assist with the language refinement and structuring of the manuscript. All the content was critically reviewed and approved by the author.

Conflicts of Interest

The author has no conflicts of interest to declare.