TBI Sex Dependently Upregulates ET-1 To Impair Autoregulation, which Is Aggravated by Phenylephrine in Males but Is Abrogated in Females
Open accessAbstract
Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Endothelin-1 (ET-1) contributes to impaired autoregulation via oxygen (O 2 - ) after TBI in piglets, but its relative role in males compared with females has not been previously investigated. Increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) sex dependently improves impairment of autoregulation after TBI through modulation of extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) upregulation, aggravated in males, but blocked in females. Activation of adenosine-5'-triphosphate (ATP) and Ca sensitive K channels produce vasodilation, contributing to autoregulation. We hypothesized that ET-1 upregulation is greater in males after TBI and that disturbed autoregulation will be prevented by Phe in a sex-dependent manner through modulation of ET-1, O 2 - , and ERK. Results show that ET-1 release was greater in males after fluid percussion injury (FPI), blunted by Phe in females, but aggravated in males. K channel vasodilation was impaired more in males than in females after TBI. Phe prevented reductions in K channel vasodilation in females, but further reduced dilation in males after TBI. Co-administration of BQ-123, U0126, or PEG-SOD (ET-1, ERK antagonist, and O 2 - scavenger) with Phe restored dilation to K agonists and hypotension in males after TBI. ERK upregulation was blocked by BQ-123 and PEG-SOD. These data indicate that TBI upregulates ET-1 more in males than in females. Elevation of CPP with Phe sex dependently prevents impairment of cerebral autoregulation after TBI through modulation of ET-1, O 2 - , and ERK mediated impairment of K channel vasodilation. These observations advocate for the consideration of development of sex-based therapies for the treatment of hemodynamic sequelae of pediatric TBI.
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Newborn female piglets had better cerebral perfusion pressure regulation after injury than males, despite their reproductively immature state.
“Moreover, newborn female piglets had better cerebral perfusion pressure regulation after injury than males, despite their reproductively immature state. 69”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [69]
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Cites
Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels
Faraci, F. M., & Heistad, D. D. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.1.53 · Cited by 781 · see citing works
The Incidence of Traumatic Brain Injury Among Children in the United States
Langlois, J. A., Rutland-Brown, W., & Thomas, K. E. (2005) · Journal of Head Trauma Rehabilitation · doi:10.1097/00001199-200505000-00006 · Cited by 428 · see citing works
Calcitonin Gene-Related Peptide and Cerebral Blood Vessels: Distribution and Vasomotor Effects
Edvinsson, L. I., Ekman, R., Jansen, I., McCulloch, J., & Uddman, R. (1987) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1987.126 · Cited by 304 · see citing works
I. Blood Pressure and Oxygenation
Bratton, S. L., Chestnut, R. M., Ghajar, J., Hammond, F. M., Harris, O. A., Härtl, R., Manley, G. T., Nemecek, A. N., Newell, D. W., Rosenthal, G., et al. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2007.9995 · Cited by 274 · see citing works
Cremer, O., Dijk, G. V., van Wensen, E., Brekelmans, G., Moons, K., Leenen, L., & Kalkman, C. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000181300.99078.b5 · Cited by 147 · see citing works
Protein Kinase C and Cerebral Vasospasm
Laher, I., & Zhang, J. H. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200108000-00001 · Cited by 135 · see citing works
Freeman, S. S., Udomphorn, Y., Armstead, W. M., Fisk, D. M., & Vavilala, M. S. (2008) · Anesthesiology · doi:10.1097/aln.0b013e31816725d7 · Cited by 108 · see citing works
Self-citationDoes induced hypertension reduce cerebral ischaemia within the traumatized human brain?
Coles, J., Steiner, L. A., Johnston, A. J., Fryer, T. D., Coleman, M. R., Smieleweski, P., Chatfield, D. A., Aigbirhio, F. I., Williams, G. B., Boniface, S. J., et al. (2004) · Brain · doi:10.1093/brain/awh268 · Cited by 82 · see citing works
Armstead, W. M. (1999) · Stroke · doi:10.1161/01.str.30.1.153 · Cited by 70 · see citing works
Self-citationRole of endothelin-1 in age-dependent cerebrovascular hypotensive responses after brain injury
Armstead, W. M. (1999) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1999.277.5.h1884 · Cited by 64 · see citing works
Self-citationKeenan, H. T., Nocera, M., & Bratton, S. L. (2005) · Pediatric Critical Care Medicine · doi:10.1097/01.pcc.0000164638.44600.67 · Cited by 63 · see citing works
Brain Injury Impairs ATP-Sensitive K+Channel Function in Piglet Cerebral Arteries
Armstead, W. M. (1997) · Stroke · doi:10.1161/01.str.28.11.2273 · Cited by 62 · see citing works
Self-citationCatalà, A., Teruel, G. C., Lasaosa, F. J. C., Odena, M. P., Noguera‐Julián, A., & Rico, A. P. (2007) · Journal of Neurosurgery Pediatrics · doi:10.3171/ped.2007.106.6.463 · Cited by 56 · see citing works
Armstead, W. M., Kiessling, J. W., Kofke, W. A., & Vavilala, M. S. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181e8ac1a · Cited by 52 · see citing works
Self-citationUse and Effect of Vasopressors after Pediatric Traumatic Brain Injury
Gennaro, J. L. D., Mack, C. D., Malakouti, A., Zimmerman, J. J., Armstead, W. M., & Vavilala, M. S. (2010) · Developmental Neuroscience · doi:10.1159/000322083 · Cited by 45 · see citing works
Self-citationHypotension dilates pial arteries by KATP and Kca channel activation
Armstead, W. M. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01146-9 · Cited by 45 · see citing works
Self-citationArmstead, W. M., Kiessling, J. W., Bdeir, K. H., Kofke, W. A., & Vavilala, M. S. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2009.1094 · Cited by 42 · see citing works
Self-citationAge‐Dependent Cerebral Hemodynamic Effects of Traumatic Brain Injury in Newborn and Juvenile Pigs
Armstead, W. M. (2000) · Microcirculation · doi:10.1111/j.1549-8719.2000.tb00123.x · Cited by 40 · see citing works
Self-citationEndothelin and the neurovascular unit in pediatric traumatic brain injury
Armstead, W. M., & Raghupathi, R. (2011) · Neurological Research · doi:10.1179/016164111x12881719352138 · Cited by 37 · see citing works
Self-citationAdelson, P. D., Bratton, S. L., Carney, N., Chesnut, R. M., du Coudray, H. E. M., Goldstein, B., Kochanek, P. M., Miller, H. C., Partington, M. D., & Selden, N. R. W. (2003) · PubMed · Cited by 35 · see citing works
Armstead, W. M. (2005) · Pathophysiology · doi:10.1016/j.pathophys.2005.01.002 · Cited by 35 · see citing works
Self-citationArmstead, W. M., Kiessling, J. W., Riley, J., Kofke, W. A., & Vavilala, M. S. (2010) · Journal of Neurotrauma · doi:10.1089/neu.2010.1581 · Cited by 34 · see citing works
Self-citationArmstead, W. M., & Vavilala, M. S. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600473 · Cited by 27 · see citing works
Self-citationIshikawa, S., Ito, H., Yokoyama, K., & Makita, K. (2009) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e31819d94e3 · Cited by 23 · see citing works
Armstead, W. M., Cines, D. B., Bdeir, K. H., Bdeir, Y., Stein, S. C., & Higazi, A. A. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.142 · Cited by 22 · see citing works
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Sorted by citations
Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know
Gupte, R. P., Brooks, W. M., Vukas, R. R., Pierce, J. D., & Harris, J. L. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6171 · Cited by 533 · see citing works
Cerebral Blood Flow Autoregulation and Dysautoregulation
Armstead, W. M. (2016) · Anesthesiology Clinics · doi:10.1016/j.anclin.2016.04.002 · Cited by 296 · see citing works
Self-citationSex-related responses after traumatic brain injury: Considerations for preclinical modeling
Späni, C. B., Braun, D. J., & Van Eldik, L. J. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.03.006 · Cited by 195 · see citing works
Neonatal cerebrovascular autoregulation
Rhee, C. J., da Costa, C. S., Austin, T., Brady, K. M., Czosnyka, M., & Lee, J. K. (2018) · Pediatric Research · doi:10.1038/s41390-018-0141-6 · Cited by 192 · see citing works
Sex Differences in Animal Models of Traumatic Brain Injury
Rubin, T. G., & Lipton, M. L. (2019) · Journal of Experimental Neuroscience · doi:10.1177/1179069519844020 · Cited by 117 · see citing works
Ma, C., Wu, X., Shen, X., Yang, Y., Chen, Z., Sun, X., & Wang, Z. (2019) · Chinese Neurosurgical Journal · doi:10.1186/s41016-019-0173-8 · Cited by 93 · see citing works
Combined Hemorrhage/Trauma Models in Pigs—Current State and Future Perspectives
Hildebrand, F., Andruszkow, H., Huber-Lang, M. S., Pape, H., & van Griensven, M. (2013) · Shock · doi:10.1097/shk.0b013e3182a3cd74 · Cited by 67 · see citing works
Sex differences in pediatric traumatic brain injury
Arambula, S. E., Reinl, E. L., Demerdash, N. E., McCarthy, M. M., & Robertson, C. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.02.016 · Cited by 65 · see citing works
Large animal models of traumatic brain injury
Dai, J., Ma, Y.-B., Le, N., Cao, J., & Wang, Y. (2018) · International Journal of Neuroscience · doi:10.1080/00207454.2017.1380008 · Cited by 42 · see citing works
Armstead, W. M., Riley, J., & Vavilala, M. S. (2013) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0b013e3182712b44 · Cited by 47 · see citing works
Self-citationScott, M. C., Prabhakara, K. S., Walters, A. J., Olson, S. D., & Cox, C. S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.753570 · Cited by 32 · see citing works
Curvello, V., Pastor, P., Hekierski, H., & Armstead, W. M. (2018) · Neurocritical Care · doi:10.1007/s12028-018-0638-1 · Cited by 26 · see citing works
Self-citationRetractedAutoregulation in paediatric TBI—current evidence and implications for treatment
Donnelly, J. E., Young, A. M. H., & Brady, K. M. (2017) · Child s Nervous System · doi:10.1007/s00381-017-3523-x · Cited by 24 · see citing works
Bohman, L., Riley, J., Milovanova, T. N., Sanborn, M. R., Thom, S. R., & Armstead, W. M. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.3885 · Cited by 18 · see citing works
Self-citationPesek, M., Kibler, K. K., Easley, R. B., Mytar, J. O., Rhee, C. J., Andropoulos, D. B., & Brady, K. M. (2014) · Neurosurgery · doi:10.1227/neu.0000000000000367 · Cited by 17 · see citing works
Armstead, W. M., Bohman, L., Riley, J., Yarovoi, S. V., Higazi, A. A., & Cines, D. B. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.2962 · Cited by 17 · see citing works
Self-citationArmstead, W., & Vavilala, M. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2018.6119 · Cited by 15 · see citing works
Self-citationLele, A. V., Alunpipatthanachai, B., Qiu, Q., Clark-Bell, C., Watanitanon, A., Moore, A. E., Chesnut, R. M., Armstead, W. M., & Vavilala, M. S. (2019) · Developmental Neuroscience · doi:10.1159/000502276 · Cited by 14 · see citing works
Self-citationHsi, P. T., Tandon, V., & Kaplan, D. L. (2025) · Scientific Reports · doi:10.1038/s41598-025-04835-2 · Cited by 11 · see citing works
Karakaya, E., Oleinik, N. V., Edwards, J. M., Tomberlin, J., Barker, R. B., Berber, B., Ericsson, M., Alsudani, H., Ergul, A., Beyaz, S., et al. (2024) · PNAS Nexus · doi:10.1093/pnasnexus/pgae018 · Cited by 12 · see citing works
Regulation of the Cerebral Circulation During Development
Koehler, R. C. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200028 · Cited by 10 · see citing works
Neuroprotection or Sex Bias: A Protective Response to Traumatic Brain Injury in the Females
Yatoo, M. I., Bahader, G. A., Beigh, S. A., Khan, A. M., James, A. W., Asmi, M. R., & Shah, Z. A. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527323666230817102125 · Cited by 9 · see citing works
Regulation of the Cerebral Circulation During Development
Koehler, R. C. (2021) · Comprehensive physiology · doi:10.1002/j.2040-4603.2021.tb00184.x · Cited by 9 · see citing works
Gu, Y., Zhang, J., Zhao, Y., Su, Y., & Zhang, Y. (2016) · Medical Science Monitor · doi:10.12659/msm.898185 · Cited by 9 · see citing works
Age and Sex Differences in Hemodynamics in a Large Animal Model of Brain Trauma
Armstead, W. M., & Vavilala, M. S. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8690-9_15 · Cited by 7 · see citing works
Self-citationCombined Hemorrhage/Trauma Models in Pigs - Current State and Future Perspectives
Hildebrand, F., Andruszkow, H., Huber-Lang, M. S., Pape, H., & van Griensven, M. (2013) · Shock · doi:10.1097/shk.0000000000000043 · Cited by 5 · see citing works
Pediatric Traumatic Brain Injury
Lee, J. K., & Koehler, R. C. (2016) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000604
Neuroprotection with phenylephrine in traumatic brain injury
Vavilala, M. S., & Sharma, D. (2012) · Critical Care Medicine · doi:10.1097/ccm.0b013e318258e9d5
Self-citation
- Authors
- Armstead, W. M., Riley, J., & Vavilala, M. S.
- Affiliations
- University of Pennsylvania (US)
- University of Washington (US)
- Corresponding author
- Armstead, William M.
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2012-05
- Volume
- 29
- Issue
- 7
- Pages
- 1483-1490
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC3335106
- OpenAlex
- W2006584979
- Cited by
- 28
- References
- 25
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 5 · 2012: 1
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HD57355)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD057355, HD 57355)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- traumatic brain injury, sex differences, endothelin-1, cerebral autoregulation, phenylephrine, cerebral perfusion pressure, ERK signaling, reactive oxygen species, fluid percussion injury, pediatric brain injury
- MeSH terms
- Animals, Animals, Newborn, Brain Injuries, Female, Homeostasis, Male, Phenylephrine, Sex Characteristics, Swine, Up-Regulation, Endothelin-1
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