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Angiopoietin/Tie2 Axis Regulates the Age-At-Injury Cerebrovascular Response to Traumatic Brain Injury

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Angiopoietin/Tie2 Axis Regulates the Age-At-Injury Cerebrovascular Response to Traumatic Brain Injury This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Angiopoietin/Tie2 axis regulates the age-at-injury cerebrovascular response to traumatic brain injury Thomas R. Brickler1, Amanda Hazy1, Fernanda Guilhaume Correa2, Rujuan Dai1, Elizabeth J.A. Kowalski1, Ross Dickerson3, John Chen1, Xia Wang1, Paul D. Morton1, Abby Whittington3, Ansar Ahmed1 and Michelle H Theus1 1The Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061 USA 2Translational Biology, Medicine, and Health Graduate Program, Virginia Tech School of Medicine, Roanoke, VA 24061 3Department of Chemical Engineering, School of Biomedical Engineering and Sciences, Virginia Tech, Roanoke, VA 24061 DOI: 10.1523/JNEUROSCI.0914-18.2018 Received: 14 June 2018 Revised: 15 July 2018 Accepted: 11 September 2018 Published: 21 September 2018 Author contributions: T.B. and M.H.T. designed research; T.B., A.H., F.G.C., R. Dai, E.K., R. Dickerman, J.C., X.W., P.M., and M.H.T. performed research; T.B., A.H., F.G.C., R. Dai, R. Dickerman, J.C., P.M., and M.H.T. analyzed data; T.B. wrote the first draft of the paper; A.H., R. Dai, P.M., A.W., A.A., and M.H.T. edited the paper; A.W. and A.A. contributed unpublished reagents/analytic tools; M.H.T. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, R01NS096281 (MHT). We recognize the Regenerative Medicine-Interdisciplinary Graduate Education Program at Virginia Tech and Institute of Critical Technology and Applied Sciences Programs for student support (TB, AH) and the Virginia-Maryland Regional College of Veterinary Medicine. We thank Dr. William Huckle for the generous gift of qPCR primers. Corresponding author: Michelle H. Theus, Ph.D. Associate Professor, Department of Biomedical Sciences and Pathobiology College of Veterinary Medicine, Virginia Tech 970 Washington Street SW (MC0910), Blacksburg, VA 24061 Tel. 540-231-0909; Fax 540-231-7425; E-mail: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.0914-18.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Angiopoietin/Tie2 axis regulates the age-at-injury cerebrovascular response to traumatic brain injury 2 3 Thomas R. Brickler1*, Amanda Hazy1*, Fernanda Guilhaume Correa2, Rujuan Dai1, Elizabeth J.A. Kowalski1, 4 Ross Dickerson3, John Chen1, Xia Wang1, Paul D. Morton1, Abby Whittington3, Ansar Ahmed1, and Michelle H 5 Theus1 6 7 8 *equal contribution 9 10 11 1The Department o f Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 12 Blacksburg, VA, 24061 USA 13 14 2Translational Biology, Medicine, and Health Graduate Program, Virginia Tech School of Medicine, Roanoke, 15 VA 24061 16 17 3Department of Chemical Engineering, School of Biomedical Engineering and Sciences, Virginia Tech, 18 Roanoke, VA 24061 19 20 21 22 Running heading: Age-at-injury response to TBI 23 24 25 26 Keywords: Tie2 receptor, angiopoietin, miRNA, vascular injury, blood brain barrier, juvenile and cerebral 27 blood flow 28 29 30 Corresponding author: 31 32 Michelle H. Theus, Ph.D. 33 Associate Professor 34 Department of Biomedical Sciences and Pathobiology 35 College of Veterinary Medicine, Virginia Tech 36 970 Washington Street SW (MC0910) 37 Blacksburg, VA 24061 38 Tel. 540-231-0909; Fax 540-231-7425; E-mail: [email protected] 39 40 Conflict of interest statement: The authors declare no competing financial interests. 41 42 Author Contribution: T.R. B., A.H., F.G.C., R.D., X.W., R.D., P.D.M., M.H.T., and E.J.A.K. performed 43 research and analyzed data. T.R.B, A.H., P.D.M., and MHT wrote the paper, A.W., A.A., P.D.M and M.H.T. 44 designed research and contributed reagents/analytic tools. 45 46 Acknowledgments: This work was supported by the National Institute of Neurological Disorders and Stroke of 47 the National Institutes of Health, R01NS096281 (MHT). We recognize the Regenerative Medicine- 48 Interdisciplinary Graduate Education Program at Virginia Tech and Institute of Critical Technology and Applied 49 Sciences Programs for student support (TB, AH) and the Virginia-Maryland Regional College of Veterinary 50 Medicine. We thank Dr. William Huckle for the generous gift of qPCR primers. 11 51 Abstract 52 While age-at-injury influences chronic recovery from traumatic brain injury (TBI), the differential 53 effects of age on early outcome remain understudied. Using a male murine model of moderate contusion 54 injury, we investigated the underlying mechanism(s) regulating the distinct response between juvenile 55 and adult TBI. We demonstrate similar biomechanical and physical properties of naïve juvenile and 56 adult brains. However, following controlled cortical impact (CCI), juvenile mice displayed reduced 57 cortical lesion formation, cell death and behavioral deficits at 4 and 14 days. Analysis of high resolution 58 laser Doppler imaging showed a similar loss of cerebral blood flow (CBF) in the ipsilateral cortex at 3 59 and 24 hours post-CCI, while juvenile mice showed enhanced subsequent restoration at 2-4 days 60 compared to adults. These findings correlated with reduced blood-brain barrier (BBB) disruption and 61 increased peri-lesional vessel density. To address whether an age-dependent endothelial cell (EC) 62 response affects vessel stability and tissue outcome, we magnetically isolated CD31-positive ECs from 63 sham and injured cortices and evaluated mRNA expression. Interestingly, we found increased transcripts 64 for BBB stability-related genes and reduced expression of BBB disrupting genes in juvenile compared to 65 adult. These differences were concomitant with significant changes in miRNA-21-5p and miR-148a 66 levels. Accompanying these findings, was robust GFAP immunoreactivity, which was not resolved by 67 day 35. Importantly, pharmacological inhibition of EC-specific Tie2 signaling abolished the juvenile 68 protective effects. These findings shed new mechanistic light on the divergent effects that age plays on 69 acute TBI outcome that are both spatial and temporal-dependent. 70 71 Significance Statement 72 Although a clear ‘window of susceptibility’ exists in the developing brain that could deter typical 73 developmental trajectories if exposed to trauma, a number of pre-clinical models have demonstrated 74 evidence of early recovery in younger patients. Our findings further demonstrate acute neuroprotection 75 and improved restoration of cerebral blood flow in juvenile mice subjected to cortical contusion injury 76 compared to adults. We also demonstrate a novel role for endothelial cell-specific Tie2 signaling in this 77 age-related response which is known to promote barrier stability, is heightened in the injured juvenile 78 vasculature and may be exploited for therapeutic interventions across the age spectrum following TBI. 79 80 Introduction 81 Traumatic brain injury (TBI) is a growing health concern that afflicts a broad range of the 82 population worldwide. (Schneier et al., 2006; Marin et al., 2014; Thurman, 2016). TBI initiates a 83 multitudinous cascade of complex biochemical events including disruption of the cerebral vasculature 2 84 and breakdown of the blood-brain barrier (BBB) that contribute to secondary injury such as hypoxia, 85 ischemia, oxidative stress and inflammation (McGinn and Povlishock, 2016; Price et al., 2016; Pearn et 86 al., 2017). While physical trauma to the developing brain may interrupt the maturation of key 87 developmental processes that support higher-order cognition in adulthood, numerous studies support an 88 age-related difference in early functional recovery. Several human studies demonstrate that increased 89 age negatively influences outcome with the greatest amount of improvement in disability seen in early 90 adolescent patients (Marquez de la Plata et al., 2008), while children under 2 years of age represent a 91 high-risk group with poorer outcome (Adelson et al., 1997). These findings are supported by pre- 92 clinical studies in swine which demonstrate greater lesion formation with increased age after acute 93 cortical impact injury (Duhaime et al., 2003; Missios et al., 2009). The mechanism(s) underlying this 94 age-at-injury difference in cortical lesion formation and functional outcome remains unknown. 95 More recently, age-specific differences in the chronic outcome from TBI have been linked to 96 dysregulation of metabolism, oxidative stress, BBB function, unresolved inflammation and β-amyloid 97 accumulation after TBI (Fan et al., 2003b; Giza and Prins, 2006; Claus et al., 2010; Kamper et al., 2013; 98 Pop et al., 2013; Moretti et al., 2015). However, in addition to the well described evolution of chronic 99 injury following juvenile TBI, there is evidence of acute tissue protection compared to adults in several 100 swine models (Duhaime et al., 2000; Duhaime et al., 2003). Age-related differences in the 101 cerebrovascular response has been suggested to play a role (Adelson et al., 1997; Armstead, 1999; 102 Durham et al., 2000; Claus et al., 2010; Curvello et al., 2017). Preserving adequate vascularization, tone 103
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