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001     276804
005     20250323000851.0
024 7 _ |a 10.1089/neu.2024.0233
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Hubertus, Vanessa
|0 0000-0002-2653-5818
|b 0
245 _ _ |a Identification of a Therapeutic Window for Neurovascular Unit Repair after Experimental Spinal Cord Injury.
260 _ _ |a Larchmont, NY
|c 2025
|b Liebert
336 7 _ |a article
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520 _ _ |a Traumatic spinal cord injury (SCI) is a devastating condition for which effective neuroregenerative and neuroreparative strategies are lacking. The post-traumatic disruption of the blood-spinal cord barrier (BSCB) as part of the neurovascular unit (NVU) is one major factor in the complex pathophysiology of SCI, which is associated with edema, inflammation, and cell death in the penumbra regions of the spinal cord adjacent to the lesion epicenter. Thus, the preservation of an intact NVU and vascular integrity to facilitate the regenerative capacity following SCI is a desirable therapeutic target. This study aims to identify a therapeutic window of opportunity for NVU repair after SCI by characterizing the timeframe of its post-traumatic disintegration and reintegration with implications for functional spinal cord recovery. Following thoracic clip-compression SCI or sham injury, adult C57BL/6J mice were followed up from one to 28 days. At one, three, seven, 14, and 28 days after SCI/sham, seven-Tesla magnetic resonance imaging (MRI), neurobehavioral analysis (Basso mouse scale, Tally subscore, CatWalk® gait analysis), and following sacrifice immunohistochemistry were performed, assessing vessel permeability via Evans blue (EVB) extravasation, (functional) vessel density, and NVU integrity. Thy1-yellow fluorescent protein+ mice were additionally implanted with a customized spinal window chamber and received longitudinal in vivo two-photon excitation imaging (2PM) with the injection of rhodamine-B-isothiocyanate-dextran for the combined imaging of axons and vasculature up to 14 days after SCI/sham injury. Post-traumatic edema formation as assessed by MRI volumetry peaked at one to three days after injury, while EVB permeability quantification revealed a thoroughly injured BSCB up to 14 days after SCI. Partial regeneration of functional vasculature via endogenous revascularization was detected after one to four weeks, however, with only 50-54% of existing vessels regaining functional perfusion. Longitudinal in vivo 2PM visualized the progressive degeneration of initially preserved spinal cord axons in the peri-traumatic zone after SCI while displaying a rarefication of functionally perfused vessels up to two weeks after injury. Neurobehavioral recovery started after one week but remained impaired over the whole observation period of four weeks after SCI. With this study, a therapeutic window to address the impaired NVU starting from the first days to two weeks after SCI is identified. A number of lines of evidence including in vivo 2PM, assessment of NVU integrity, and neurobehavioral assessments point to the critical nature of targeting the NVU to enhance axonal preservation and regeneration after SCI. Continuous multifactorial therapy applications targeting the integrity of the NVU over the identified therapeutic window of opportunity appears promising to ameliorate functional vessel perseverance and the spinal cord's regenerative capacity.
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650 _ 7 |a neurovascular unit
|2 Other
650 _ 7 |a spinal cord injury
|2 Other
650 _ 7 |a spinal cord regeneration
|2 Other
650 _ 7 |a vascular injury
|2 Other
650 _ 7 |a vascular regeneration
|2 Other
650 _ 2 |a Spinal Cord Injuries: physiopathology
|2 MeSH
650 _ 2 |a Spinal Cord Injuries: diagnostic imaging
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Recovery of Function: physiology
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Magnetic Resonance Imaging
|2 MeSH
650 _ 2 |a Nerve Regeneration: physiology
|2 MeSH
650 _ 2 |a Time Factors
|2 MeSH
700 1 _ |a Meyer, Lea
|b 1
700 1 _ |a Waldmann, Lilly
|b 2
700 1 _ |a Roolfs, Laurens
|b 3
700 1 _ |a Taheri, Nima
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700 1 _ |a Kersting, Katharina
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700 1 _ |a von Bronewski, Emily
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700 1 _ |a Nieminen-Kelhä, Melina
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700 1 _ |a Kremenetskaia, Irina
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700 1 _ |a Uhl, Christian
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700 1 _ |a Fiedler, Kim C
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700 1 _ |a Ode, Jan-Erik
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700 1 _ |a Rex, Andre
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700 1 _ |a Prüß, Harald
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700 1 _ |a Rakhymzhan, Asylkhan
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700 1 _ |a Hauser, Anja E
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700 1 _ |a Niesner, Raluca
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700 1 _ |a Heppner, Frank L
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700 1 _ |a Fehlings, Michael G
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700 1 _ |a Vajkoczy, Peter
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773 _ _ |a 10.1089/neu.2024.0233
|g Vol. 42, no. 3-4, p. 212 - 228
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