Angiogenesis and Hypoxia Biomarkers Are Dysregulated in Progressive Multiple Sclerosis.

Abstract

Background and objectives: 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).

Methods: 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.

Results: 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 (p = 0.02) and 48 (p = 0.02) weeks and predicted disability worsening (hazard ratio 0.31, 95% CI 0.14-0.69, p = 0.034). Conversely, higher leptin levels trended to predict cognitive worsening on the symbol digit modalities test.

Discussion: 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.