We thank Sim4Life by ZMT, www.zurichmedtech.com for their support. We thank Brian K. Kwon for critically reading the manuscript and his insightful suggestions.

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b−) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (−93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

Spinal cord injury (SCI) is a devastating neurological condition for which there is no effective treatment to restore neurological function. The development of new treatments for those with SCI may be hampered by the insensitivity of clinical tools to assess motor function in humans. Treatments aimed at preserving neuronal function through anti-inflammatory pathways (i.e., neuroprotection) have been a mainstay of pre-clinical SCI research for decades. Minocycline, a clinically available antibiotic agent with anti-inflammatory properties, has demonstrated promising neuroprotective effects in a variety of animal models and improved motor recovery in a Phase-2 human trial. Here, we leveraged our recently developed T3 severe contusion model in the rat to determine the ability of minocycline to preserve descending sympathoexcitatory axons and improve cardiovascular control after SCI. Forty-one male Wistar rats were randomized to either a treatment group (minocycline; n = 20) or a control group (vehicle; n = 21). All rats received a severe T3 contusion. Minocycline (or vehicle) was administered intraperitoneally at one hour post-injury (90 mg/kg), then every 12 h for two weeks (45 mg/kg). Neuroanatomical correlates (lesion area, descending sympathoexcitatory axons) were assessed, in addition to an assessment of cardiovascular control (hemodynamics, autonomic dysreflexia) and motor behavior. Here, we show that minocycline reduces lesion area, increases the number of descending sympathoexctitatory axons traversing the injury site, and ultimately reduces the severity of autonomic dysreflexia. Finally, we show that autonomic dysreflexia is a more sensitive marker of treatment stratification than motor function.