Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature

Rahul Sachdeva; Mengyao Jia; Shaoxun Wang; Andrew Yung; Mei Mu Zi Zheng; Amanda H.X. Lee; Aaron Monga; Sarah Leong; Piotr Kozlowski; Fan Fan; Richard J. Roman; Aaron A. Phillips; Andrei V. Krassioukov

doi:10.1089/neu.2019.6913

Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature

Rahul Sachdeva, Mengyao Jia, Shaoxun Wang, Andrew Yung, Mei Mu Zi Zheng, Amanda H.X. Lee, Aaron Monga, Sarah Leong, Piotr Kozlowski, Fan Fan, Richard J. Roman, Aaron A. Phillips, Andrei V. Krassioukov

Rehabilitation Medicine

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.

Original language	English
Pages (from-to)	1963-1970
Number of pages	8
Journal	Journal of Neurotrauma
Volume	37
Issue number	18
DOIs	https://doi.org/10.1089/neu.2019.6913
State	Published - Sep 15 2020

Bibliographical note

Publisher Copyright:
© Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.

Funding

The present study was supported by funds from the Heart and Stroke Foundation (G-16-00012571) and Canadian Institutes of Health Research (389694). Dr. Sachdeva is supported by Postdoctoral Fellowships from the Craig H. Neilsen Foundation (455064), Canadian Institutes of Health Research (415366), Michael Smith Foundation for Health Research (18408) and University of British Columbia (Bluma Tischler Postdoctoral Fellowship). The Phillips Lab is supported by the Wings for Life Foundation (Project Grant 202), Compute Canada (Resources for Research Groups nnu-172), Natural Sciences and Engineering Research Council (Canada; Discovery Grant RGPIN/03771-2018), the Canadian Institutes of Health Research (Project Grant 159573), Alberta Innovates Health Solutions, Campus Alberta Neuroscience, the Libin Cardiovascular Institute of Alberta, the Hotchkiss Brain Institute, and the Rick Hansen Institute. Dr. Fan and Roman Labs were supported by grants AG050049 (F.F.), AG057842 (F.F.) and HL138685 (R.J.R.) from the National Institutes of Health.

Funders	Funder number
Libin Cardiovascular Institute of Alberta
National Institutes of Health (NIH)
National Institute on Aging	R01AG057842
Heart and Stroke Foundation of Canada	G-16-00012571
Craig H. Neilsen Foundation	455064, 415366
Wings for Life Spinal Cord Research Foundation	202
Rick Hansen Institute	AG050049, HL138685, AG057842
Compute Canada	nnu-172
Hotchkiss Brain Institute
Campus Alberta Neuroscience
Canadian Institutes of Health Research	389694
Natural Sciences and Engineering Research Council of Canada	RGPIN/03771-2018, 159573
Alberta Innovates - Health Solutions
Michael Smith Foundation for Health Research	18408
Univ. of Northern British Columbia

Keywords

cerebrovascular deficit
cognitive impairment
endothelial dysfunction
spinal cord injury
vascular fibrosis

ASJC Scopus subject areas

Clinical Neurology

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10.1089/neu.2019.6913

Cite this

Sachdeva, R., Jia, M., Wang, S., Yung, A., Zheng, M. M. Z., Lee, A. H. X., Monga, A., Leong, S., Kozlowski, P., Fan, F., Roman, R. J., Phillips, A. A., & Krassioukov, A. V. (2020). Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature. Journal of Neurotrauma, 37(18), 1963-1970. https://doi.org/10.1089/neu.2019.6913

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abstract = "Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55\% (SCI vs. control: 13.4 ± 1.9\% vs. 29.63 ± 2.8\%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50\% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37\% (SCI vs. control: 30.5 ± 2.9\% vs. 42.0 ± 4.0\%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32\% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.",

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Sachdeva, R, Jia, M, Wang, S, Yung, A, Zheng, MMZ, Lee, AHX, Monga, A, Leong, S, Kozlowski, P, Fan, F, Roman, RJ, Phillips, AA & Krassioukov, AV 2020, 'Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature', Journal of Neurotrauma, vol. 37, no. 18, pp. 1963-1970. https://doi.org/10.1089/neu.2019.6913

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T1 - Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature

AU - Sachdeva, Rahul

AU - Jia, Mengyao

AU - Wang, Shaoxun

AU - Yung, Andrew

AU - Zheng, Mei Mu Zi

AU - Lee, Amanda H.X.

AU - Monga, Aaron

AU - Leong, Sarah

AU - Kozlowski, Piotr

AU - Fan, Fan

AU - Roman, Richard J.

AU - Phillips, Aaron A.

AU - Krassioukov, Andrei V.

PY - 2020/9/15

Y1 - 2020/9/15

N2 - Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.

AB - Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.

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KW - cognitive impairment

KW - endothelial dysfunction

KW - spinal cord injury

KW - vascular fibrosis

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Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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