Water treadmill training attenuates blood-spinal cord barrier disruption in rats by promoting angiogenesis and inhibiting matrix metalloproteinase-2/9 expression following spinal cord injury

Abstract

Background The permeability of the blood-spinal cord barrier (BSCB) is mainly determined by junction complexes between adjacent endothelial cells (ECs), including tight junctions (TJs) and adherens junctions (AJs), which can be severely damaged after spinal cord injury (SCI). Exercise training is a recognized method for the treatment of SCI. The destruction of the BSCB mediated by matrix metalloproteinases (MMPs) leads to inflammation, neurotoxin production, and neuronal apoptosis. The failure of new blood vessels to effectively regenerate is also an important cause of delayed recovery after SCI. For the first time, we introduced water treadmill training (TT) to help SCI rats successfully exercise and measured the effects of TT in promoting recovery after SCI and the possible mechanisms involved. Methods Sprague-Dawley (200–250 g) rats were randomly divided into the following three groups: sham operated, SCI, and SCI + TT. Animals were sacrificed at 7 or 14 days post-surgery. The degree of neurological deficit, tissue morphology and BSCB permeability were assessed by the Basso-Beattie-Bresnahan (BBB) motor function scale and appropriate staining protocols, and apoptosis, protein expression and vascular EC ultrastructure were assessed by TUNEL staining, Western blotting, immunofluorescence and transmission electron microscopy (TEM). Results Our experiments showed that TT reduced permeability of the BSCB and decreased structural tissue damage. TT significantly improved functional recovery when compared with that in the SCI group; TJ and AJ proteins expression increased significantly after TT, and training reduced apoptosis induced by SCI. TT could promote angiogenesis, and MMP-2 and MMP-9 expression was significantly inhibited by TT. Conclusions The results of this study indicate that TT promotes functional recovery for the following reasons: TT (1) protects residual BSCB structure from further damage, (2) promotes vascular regeneration, and (3) inhibits MMP-2/9 expression to mitigate BSCB damage.

Water Treadmill Training Ameliorates Neurite Outgrowth Inhibition Associated with NGR/RhoA/ROCK by Inhibiting Astrocyte Activation following Spinal Cord Injury

“…It has also been reported that rehabilitative training can promote axonal regeneration in peripheral nerve injury [ 21 ], but the specific mechanism by which rehabilitative training affects axonal outgrowth in the CNS has not been determined. In this study, we combined a treadmill with swimming (to avoid potential injuries caused by early intensive training) and used the water treadmill [ 22 ] to explore the mechanism underlying neurite outgrowth after SCI.…”

Revascularization After Traumatic Spinal Cord Injury

“…Locomotor training combined with epidural stimulation, moreover, increases capillary distribution across the muscle after SCI (Kissane et al, 2019). Recently, researchers have found that water treadmill training (TT) reduces BSCB permeability after SCI by inhibiting MMP-2/9 expression (Ying et al, 2020). TT also triggers the BDNF/TrkB-CREB signaling pathway to ameliorate BSCB disruption following SCI (Ying et al, 2021).…”

“…Fibrin (Yao et al, 2018a;Loureiro et al, 2019), HA (Wei et al, 2010), Collagen (Wang et al, 2018) Synthetic materials PLL (Patist et al, 2004), PLGA (Yu et al, 2016b;Ropper et al, 2017) Physical stimulation CMH (Halder et al, 2018), Training (Kissane et al, 2019;Ying et al, 2020Ying et al, , 2021, tsDCS (Samaddar et al, 2017) (tsDCS) promotes blood flow to modulate neural cell migration and proliferation after SCI (Samaddar et al, 2017).…”

Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury

“…VEGF promotes endothelial cell proliferation, vascularization, and angiogenesis, and is upregulated by exercise via lactate receptors expressed in the blood–brain barrier [ 172 ]. After SCI, the exercise-induced increase in VEGF is associated with enhanced expression of tight junctions and adherens junctions, which reduces blood–spinal-cord barrier permeability and improves locomotor recovery [ 173 ]. This effect was further shown to rely on BDNF/TrkB signaling [ 47 ], as well as inhibition of matrix metalloproteinases (MMPs) [ 173 ], which restructure extracellular matrices and damage the blood–spinal-cord barrier after SCI [ 174 , 175 ].…”

“…After SCI, the exercise-induced increase in VEGF is associated with enhanced expression of tight junctions and adherens junctions, which reduces blood–spinal-cord barrier permeability and improves locomotor recovery [ 173 ]. This effect was further shown to rely on BDNF/TrkB signaling [ 47 ], as well as inhibition of matrix metalloproteinases (MMPs) [ 173 ], which restructure extracellular matrices and damage the blood–spinal-cord barrier after SCI [ 174 , 175 ]. Interestingly, another study found that after SCI, proliferating endothelial cells located in the core of the lesion upregulate CD200, which hinders inflammation [ 176 ], while yet another study found that treadmill exercise upregulates both CD200 and its receptor after stroke in rats [ 177 ].…”