Analysis of the spatiotemporal dynamic of vascular injury and revascularization following experimental spinal cord injury
Christian Joachim Entenmann (Berlin), Emily von Bronewski (Berlin), Lily Waldmann (Berlin), Lea Meyer (Berlin), Katharina Kersting (Berlin), Laurens Roolfs (Berlin), Melina Nieminen-Kelhä (Berlin), Irina Kremenetskaia (Berlin), Frank Heppner (Berlin), Michael G. Fehlings (Toronto / CA), Peter Vajkoczy (Berlin), Vanessa Hubertus (Berlin)
Traumatic Spinal Cord Injury (SCI) remains a global burden due to the lack of restorative therapies. The early loss of functional vasculature is part of a complex secondary injury cascade that leads to ongoing tissue loss, spreading the injury to regions formerly unharmed. A deeper understanding of the pathophysiology and its timeframe is essential in the search for restorative therapies. Specifically, when evaluating the effects of local therapies, defining the regional extent of vascular injury is necessary. This study aims to characterize the temporal and spatial aspects of vascular injury and revascularization following experimental SCI in the mouse.
Adult C57BL/6J mice (n=26) were subjected to thoracic (Th6/7) clip-compression SCI via modified aneurysm clip (5g, 60s) or sham injury (laminectomy). At days 1, 3, 7, 14, and 28 post surgery, animals (n=4/group) were sacrificed via intracardial fluorescein isothiocyanate (FITC)-Lectin perfusion to assess functional vasculature. Histological analysis (CD31, FITC-Lectin, Ki-67) was conducted to assess temporal and spatial vascular changes and endogenous revascularization within the epicenter of injury (+/-0,5mm) and two subsequent spinal cord regions with increasing distance from trauma epicenter (region 1: +/- 0,5-1mm, region 2: +/-1-3mm)
Loss of functional vasculature as measured by FITC-Lectin+ vessels was instantly assessable in trauma epicenter and subsequent region 1, being most severe at d3 (p<0.01). In region 2 significant loss of functional vasculature occurred only from d3 on (p=0.0427) and was restituted already on d7 (p=0.1159), while region 1 and trauma epicenter were restituted at d28 (p=0.2713, p=0.1251 respectively). Overall vessel density as measured by CD31+ signals was returned to baseline quicker (d3 epicenter, d14 regions 1+2). Revascularization as indicated by Ki67+ endothelial cells occurred in all regions after 3d (p<0.01), being most prominent in region 2.
These findings deliver further insights into the temporal and spatial dynamics of the loss of functional vasculature and its restoration by endogenous revascularization following SCI. We demonstrate that vascular injury is most prominent in the first days after injury and spreads to wider regions surrounding the injury. While partial vascular regeneration occurs, it remains incomplete. The development of local therapies to ameliorate these events remain desirable.
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