Yong Heather Y F, Jain Rajiv W, Goiko Maria, Batty Nicholas J, Phillips Serena, Ghuman Mankarman, Koch Marcus Werner, Camara-Lemarroy Carlos
Department of Clinical Neurosciences, University of Calgary, Canada.
Cumming School of Medicine, University of Calgary, Canada; and.
Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6):e200477. doi: 10.1212/NXI.0000000000200477. Epub 2025 Sep 18.
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative CNS disorder characterized by a state of "virtual hypoxia." Angiogenesis, one of the main homeostatic responses to hypoxia, has been implicated in the pathophysiology of MS. The study objective was to determine whether angiogenic and hypoxia-related molecules are dysregulated in the serum and CNS of patients with progressive multiple sclerosis (PMS).
Baseline serum samples were obtained from a phase II trial of Ibudilast in PMS (n = 203 analyzed) and matched to healthy controls (n = 53). Participants on previous therapeutics (interferons or glatiramer acetate) were excluded from analysis (n = 131). Angiogenic factors were measured using a commercially available bead-based multiplex assay, and hypoxia biomarkers were measured using a custom bead-based multiplex assay. To interrogate the expression of selected hypoxia and angiogenic markers in the CNS, we analyzed publicly available transcriptomic databases and in-house generated data from normal appearing white matter of 2 SPMS donors and 2 nonneurologic disease controls.
Circulating markers of hypoxia (such as hypoxia inducible factor-1-a, heme oxygenase-1, and heat shock protein-90) were increased in serum. Conversely, markers of angiogenesis (such as vascular endothelial growth factor-A [VEGF-A], heparin-binding epidermal growth factor, and hepatocyte growth factor) were reduced suggesting a blunting of the angiogenic response. Several of these changes were confirmed in the PMS CNS transcriptome. Lower levels of VEGF-A were associated with disability worsening on the timed-25 foot-walk test at 24 ( = 0.02) and 48 ( = 0.02) weeks and predicted disability worsening (hazard ratio 0.31, 95% CI 0.14-0.69, = 0.034). Conversely, higher leptin levels trended to predict cognitive worsening on the symbol digit modalities test.
Hypoxia-angiogenesis signals are dysregulated in PMS. Increased hypoxia and an insufficient angiogenic adaptive response may play a role in PMS pathophysiology and be a relevant pathway, both in understanding disease mechanisms and as a possible therapeutic target.
多发性硬化症（MS）是一种神经炎症性和神经退行性中枢神经系统疾病，其特征为“虚拟缺氧”状态。血管生成作为对缺氧的主要稳态反应之一，已被认为与MS的病理生理学有关。本研究的目的是确定血管生成相关分子和缺氧相关分子在进行性多发性硬化症（PMS）患者的血清和中枢神经系统中是否失调。
从一项关于异丁司特治疗PMS的II期试验中获取基线血清样本（分析了203例），并与健康对照（53例）进行匹配。排除之前接受过治疗（干扰素或醋酸格拉替雷）的参与者（131例）进行分析。使用市售的基于微珠的多重检测法测量血管生成因子，使用定制的基于微珠的多重检测法测量缺氧生物标志物。为了研究中枢神经系统中选定的缺氧和血管生成标志物的表达，我们分析了公开可用的转录组数据库以及来自2例继发进展型多发性硬化症（SPMS）供体和2例非神经系统疾病对照的正常外观白质的内部生成数据。
血清中缺氧循环标志物（如缺氧诱导因子-1-α、血红素加氧酶-1和热休克蛋白-90）增加。相反，血管生成标志物（如血管内皮生长因子-A [VEGF-A]、肝素结合表皮生长因子和肝细胞生长因子）减少，表明血管生成反应减弱。其中一些变化在PMS中枢神经系统转录组中得到证实。较低水平的VEGF-A与24周（P = 0.02）和48周（P = 0.02）时定时25英尺步行试验中的残疾恶化相关，并预测残疾恶化（风险比0.31，95%可信区间0.14 - 0.69，P = 0.034）。相反，较高的瘦素水平倾向于预测符号数字模态试验中的认知恶化。
PMS中缺氧-血管生成信号失调。缺氧增加和血管生成适应性反应不足可能在PMS病理生理学中起作用，并且在理解疾病机制和作为可能的治疗靶点方面都是一个相关途径。
