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The recognition that SMA is a multisystem disorder has profound implications for how the disease is studied and treated. For decades, the clinical focus rested squarely on the motor neuron and the neuromuscular junction, an emphasis that was understandable given that weakness and respiratory failure dominate the clinical picture. Yet as the review by Parson and Allardyce makes clear, the vasculature represents a tissue system that is both ubiquitously distributed and exquisitely sensitive to the loss of survival motor neuron protein. Endothelial cells, which line every blood vessel in the body, depend on precisely regulated RNA metabolism, cytoskeletal organization, and bioenergetic function, all of which are processes in which SMN protein plays a documented role. This convergence of SMN-dependent cellular functions within endothelial biology provides a coherent mechanistic rationale for why vascular abnormalities appear repeatedly across so many affected organs in SMA, from the spinal cord and skeletal muscle to the heart, kidney, gastrointestinal tract, and spleen.

One of the most compelling aspects of the vascular hypothesis in SMA is the consistency of the experimental findings across model systems. Studies in mouse models of SMA have demonstrated defects in angiogenesis, the process by which new blood vessels form from pre-existing vessels, as well as impaired vascular maturation, in which nascent vessels fail to acquire the structural features of stable, mature vasculature. Vessel stability itself is compromised, meaning that vessels that do form may regress or become leaky over time. These are not trivial defects. Angiogenesis is essential during development and remains important throughout life for tissue repair and adaptation to metabolic demand. When angiogenesis is impaired in a growing organism, as it is in infants with severe SMA, the consequences for organ development can be substantial and potentially irreversible if not addressed within a critical developmental window.

The consequences of endothelial dysfunction extend well beyond the simple mechanical failure of blood vessels. Endothelial cells regulate vascular tone, control the trafficking of cells and molecules across the vessel wall, and actively communicate with surrounding parenchymal cells through secreted signals. When endothelial function is compromised, tissue perfusion declines, leading to local hypoxia that can stress metabolically demanding cells such as motor neurons and cardiomyocytes. Barrier integrity may be disrupted, which is particularly consequential in the central nervous system where the blood-brain barrier and blood-spinal cord barrier protect vulnerable neural tissue from circulating inflammatory mediators and potentially toxic blood-borne substances. Furthermore, dysfunctional endothelium can shift inflammatory signaling toward a pro-inflammatory state, creating a permissive environment for tissue damage that compounds the primary effects of SMN deficiency in neurons and muscle.

The evidence from patient-derived biomarkers is especially significant because it bridges the gap between experimental models and clinical reality. Retinal vascular imaging offers a non-invasive window into the microvasculature, allowing clinicians to visualize vessel architecture and detect abnormalities that may reflect systemic endothelial dysfunction. The identification of elevated circulating endothelial cells in SMA patients is particularly noteworthy. These cells, which are shed into the bloodstream when endothelial layers are damaged or destabilized, serve as a measurable indicator of ongoing vascular injury. Their presence in patient circulation suggests that endothelial dysfunction is not merely a developmental phenomenon confined to the most severe cases, but a persistent feature of the disease that may continue to operate even as other aspects of pathology are modified by treatment.

This raises a critical question that the review addresses directly: are current SMN-restorative therapies adequately addressing vascular pathology? Nusinersen, an antisense oligonucleotide delivered by intrathecal injection, modifies SMN2 splicing to increase production of full-length SMN protein. Risdiplam, an orally administered small molecule, achieves the same molecular goal through a different mechanism. Onasemnogene abeparvovec delivers a functional copy of the SMN1 gene via viral vector. All three approaches have produced unprecedented clinical benefits, transforming SMA from a uniformly fatal disease into a treatable condition. However, each therapy was designed and evaluated primarily with motor neuron rescue in mind. The extent to which these therapies restore SMN expression in endothelial cells, and whether such restoration is sufficient to reverse established vascular abnormalities, remains an open question with significant clinical implications.

The pharmacological properties of each therapy create distinct challenges for vascular targeting. Intrathecal delivery of nusinersen concentrates the drug within the central nervous system, raising questions about whether peripheral endothelial cells receive adequate exposure. Risdiplam, being orally bioavailable, distributes more broadly throughout the body, but the degree to which it reaches therapeutically meaningful levels within vascular tissue is not fully characterized. Viral vector delivery in onasemnogene abeparvovec depends on the tropism of the vector for specific cell types, and the efficiency of transduction in endothelial cells compared with motor neurons is an area requiring further investigation. These considerations suggest that even as motor neuron function improves dramatically under current treatment paradigms, vascular pathology may persist as a source of ongoing morbidity that requires direct therapeutic attention.

The timing of therapeutic intervention is another dimension that deserves careful consideration. SMN expression is highest during embryonic and early postnatal development, with a progressive decline into adulthood in both humans and mice. This developmental pattern suggests that SMN plays particularly important roles during periods of rapid growth and organogenesis, precisely when the vasculature is being established and remodeled. Newborn screening programs that identify SMA before symptom onset have enabled earlier treatment initiation, and this has been associated with substantially better outcomes. However, even with presymptomatic treatment, the question remains whether vascular development proceeds normally when SMN is restored, or whether subtle vascular deficits persist that may influence long-term tissue health. The inter-individual variation in treatment response documented in patient-derived fibroblast studies, influenced by baseline SMN levels, SMN2 copy number, and age, suggests that the vascular response to therapy may also vary considerably between patients.

The organ-specific nature of vascular pathology in SMA adds further complexity. The central nervous system is particularly vulnerable to vascular compromise because of its high energy requirements and dependence on the integrity of the blood-CNS barriers. Motor neurons, with their exceptionally long axons and high metabolic demands, are among the most energy-intensive cells in the body, and any reduction in perfusion or increase in local hypoxia could stress these cells beyond their adaptive capacity. Skeletal muscle, which depends on a rich capillary network for oxygen and nutrient delivery during contraction, may suffer functional consequences when vascular supply is compromised, potentially exacerbating the atrophy that results from denervation. The heart, with its continuous contractile activity and high oxygen consumption, is similarly dependent on adequate vascular function, and cardiac pathology is a well-recognized feature of severe SMA. The kidney, gastrointestinal tract, and spleen each have specialized vascular architectures that serve their unique physiological functions, and disruption of these architectures could contribute to the systemic manifestations of the disease.

The inflammatory dimension of vascular pathology deserves particular attention in the context of SMA. Endothelial cells are not passive conduits but active participants in immune regulation, expressing adhesion molecules that control leukocyte trafficking and secreting cytokines and chemokines that shape the local inflammatory environment. When endothelial function is disrupted, the balance between pro-inflammatory and anti-inflammatory signaling may shift, creating conditions that favor tissue damage. In the central nervous system, where the blood-brain barrier normally restricts immune cell entry, endothelial dysfunction could permit increased immune surveillance and potentially neuroinflammation, processes that are increasingly recognized as contributors to neurodegeneration. In peripheral tissues, altered inflammatory signaling could amplify muscle damage and impair regenerative capacity, compounding the effects of denervation on muscle health.

Looking forward, the vascular hypothesis of SMA pathogenesis suggests several avenues for therapeutic development that complement existing SMN-restorative strategies. Directly targeting endothelial function, whether through agents that promote vascular stability, enhance angiogenic signaling, or protect barrier integrity, could address a dimension of the disease that current therapies may not fully resolve. Biomarker-guided approaches, using retinal vascular imaging and circulating endothelial cell counts to monitor vascular health over time, could enable clinicians to identify patients whose vascular pathology persists despite adequate SMN restoration and to evaluate the efficacy of vascular-targeted interventions. The integration of vascular assessment into standard clinical care for SMA patients represents a logical next step that builds on the growing recognition of SMA as a truly multisystem disorder.

The long-term implications of vascular pathology in SMA are becoming increasingly relevant as patient survival and life expectancy continue to improve. Adults with SMA who have been treated from infancy or childhood are now entering developmental stages that were previously unreachable, and the persistence of vascular abnormalities into adulthood could influence tissue health across the lifespan. Understanding whether vascular pathology that is established during development can be fully reversed by later treatment, or whether it leaves lasting deficits that require ongoing management, is essential for planning long-term care. The review by Parson and Allardyce provides a timely synthesis of the evidence needed to guide this understanding, identifying key knowledge gaps and framing the questions that future research must address to ensure that therapeutic advances in SMA continue to evolve in step with the full spectrum of disease pathology.

Subject of Research: …

Article Title: The role of vascular pathology in SMA: implications for pathogenesis and treatment

Article References: Parson, S. H., & Allardyce, H. (2026). The role of vascular pathology in SMA: implications for pathogenesis and treatment. Frontiers in Cellular Neuroscience, 20, Article 1933459. https://doi.org/10.3389/fncel.2026.1933459

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1933459

Keywords: role, vascular, pathology, implications, pathogenesis, treatment, scientific research