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Patients with progressive multiple sclerosis display disrupted hypoxia–angiogenesis balance, with low VEGF-A predicting clinical worsening.
A new analysis highlights a significant disruption in hypoxia- and angiogenesis-related pathways in progressive multiple sclerosis (PMS), offering fresh insight into disease mechanisms and potential therapeutic targets.
Multiple sclerosis (MS) is a long-term neuroinflammatory and neurodegenerative ailment of the central nervous system (CNS). In progressive forms of the disease, mounting evidence suggests the presence of a state of “virtual hypoxia,” where impaired oxygen delivery and utilization contribute to ongoing neurodegeneration. Angiogenesis—the formation of novel blood vessels—is a primary physiological response to hypoxia, yet its role in PMS has remained unclear. Hence, this study sought to determine whether molecules linked to hypoxia and angiogenesis are dysregulated in the serum and CNS of PMS sufferers.
Baseline serum samples were analyzed from 203 patients enrolled in a phase II clinical trial of ibudilast in PMS and compared with samples from 53 healthy controls. To avoid confounding effects, participants previously treated with interferons or glatiramer acetate were eliminated from the analysis (n = 131). Angiogenic factors were quantified via a commercially available bead-based multiplex assay, while hypoxia-related biomarkers were measured via a custom bead-based multiplex platform.
To explore whether peripheral findings were reflected in the CNS, researchers also examined publicly available transcriptomic datasets along with in-house gene expression data derived from normal-appearing white matter of two secondary progressive MS donors and two non-neurologic disease controls.
Key findings
The analysis revealed a clear imbalance between hypoxia signaling and angiogenic response in PMS:
Importantly, clinical correlations strengthened the biological significance of these findings. Lower serum VEGF-A levels were linked with worsening disability on the timed 25-foot walk test at both 24 weeks (p = 0.02) and 48 weeks (p = 0.02). Reduced VEGF-A also predicted disability progression over time (hazard ratio 0.31, p = 0.034).
In contrast, higher leptin levels exhibited a trend toward predicting cognitive decline, as measured by the Symbol Digit Modalities Test. To sum up, hypoxia–angiogenesis signaling is markedly dysregulated in PMS. Increased hypoxic stress coupled with an inadequate angiogenic adaptive response may contribute directly to disease progression and disability accumulation in PMS.
Neurology: Neuroimmunology & Neuroinflammation
Angiogenesis and Hypoxia Biomarkers Are Dysregulated in Progressive Multiple Sclerosis
Heather Y.F. Yong et al.
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