Endothelial Cells and the Blood-Brain Barrier: Critical Determinants of Ineffective Reperfusion in Stroke

Overview

Journal Eur J Neurosci

Specialty Neurology

Date 2025 Feb 12

PMID 39935212

Authors

Xiang Li

Leticia Simo

Qianhui Zhao

Enoch Gene Kim

Yuchuan Ding

Xiaokun Geng

Affiliations

Soon will be listed here.

Abstract

Ineffective reperfusion remains a critical challenge in neurointerventional treatment following ischemic stroke, with the integrity of the blood-brain barrier (BBB) being a key determinant of patient outcomes. This review explores the distinctive characteristics and roles of brain endothelial cells (ECs) in the context of stroke and ineffective reperfusion. We examine the unique properties of brain ECs compared to their counterparts in other tissues, focusing on their pathophysiological changes, functional impairments and the inflammatory cascades that follow stroke. Differences in gene expression between brain ECs and those in other organs offer deeper insights into their role in neuroprotective therapies. Additionally, drawing parallels between brain ECs and ECs from organs with similar ischemia-reperfusion injury profiles may inspire novel therapeutic approaches. This review highlights the critical importance of understanding the nuanced roles of ECs in BBB regulation, which ultimately impacts reperfusion outcomes.

References

Bui T, Wiesolek H, Sumagin R . ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. J Leukoc Biol. 2020; 108(3):787-799. PMC: 7977775. DOI: 10.1002/JLB.2MR0220-549R. View

Jiang X, Andjelkovic A, Zhu L, Yang T, Bennett M, Chen J . Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2017; 163-164:144-171. PMC: 5886838. DOI: 10.1016/j.pneurobio.2017.10.001. View

Bosche B, Schafer M, Graf R, Hartel F, Schafer U, Noll T . Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells. Biochem Biophys Res Commun. 2013; 434(2):268-72. DOI: 10.1016/j.bbrc.2013.03.047. View

Galea I . The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol. 2021; 18(11):2489-2501. PMC: 8481764. DOI: 10.1038/s41423-021-00757-x. View

Fang J, Guo Y, Tan S, Li Z, Xie H, Chen P . Autologous Endothelial Progenitor Cells Transplantation for Acute Ischemic Stroke: A 4-Year Follow-Up Study. Stem Cells Transl Med. 2018; 8(1):14-21. PMC: 6312444. DOI: 10.1002/sctm.18-0012. View

Gong S, Cao G, Li F, Chen Z, Pan X, Ma H . Endothelial Conditional Knockdown of NMMHC IIA (Nonmuscle Myosin Heavy Chain IIA) Attenuates Blood-Brain Barrier Damage During Ischemia-Reperfusion Injury. Stroke. 2021; 52(3):1053-1064. DOI: 10.1161/STROKEAHA.120.031410. View

Li X, Ding Y, Haddad Y, Geng X . Greater Omentum: Multifaceted Interactions in Neurological Recovery and Disease Progression. Aging Dis. 2024; 15(6):2381-2394. PMC: 11567243. DOI: 10.14336/AD.2024.0213. View

Sadeghian N, Shadman J, Moradi A, Golmohammadi M, Panahpour H . Calcitriol protects the Blood-Brain Barrier integrity against ischemic stroke and reduces vasogenic brain edema via antioxidant and antiapoptotic actions in rats. Brain Res Bull. 2019; 150:281-289. DOI: 10.1016/j.brainresbull.2019.06.010. View

Gadani S, Walsh J, Lukens J, Kipnis J . Dealing with Danger in the CNS: The Response of the Immune System to Injury. Neuron. 2015; 87(1):47-62. PMC: 4491143. DOI: 10.1016/j.neuron.2015.05.019. View

10.

Lundberg J, Weitzberg E, Gladwin M . The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008; 7(2):156-67. DOI: 10.1038/nrd2466. View

11.

Przysinda A, Feng W, Li G . Diversity of Organism-Wide and Organ-Specific Endothelial Cells. Curr Cardiol Rep. 2020; 22(4):19. PMC: 7894984. DOI: 10.1007/s11886-020-1275-9. View

12.

Gladwin M, Tejero J . Nitrite-NO bailout for a NOS complex too big to fail. Nat Med. 2011; 17(12):1556-7. DOI: 10.1038/nm.2591. View

13.

Perez-Pinera P, Berenson J, Deuel T . Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis. Curr Opin Hematol. 2008; 15(3):210-4. DOI: 10.1097/MOH.0b013e3282fdc69e. View

14.

Bernardo-Castro S, Sousa J, Bras A, Cecilia C, Rodrigues B, Almendra L . Pathophysiology of Blood-Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery. Front Neurol. 2020; 11:594672. PMC: 7756029. DOI: 10.3389/fneur.2020.594672. View

15.

An L, Shen Y, Chopp M, Zacharek A, Venkat P, Chen Z . Deficiency of Endothelial Nitric Oxide Synthase (eNOS) Exacerbates Brain Damage and Cognitive Deficit in A Mouse Model of Vascular Dementia. Aging Dis. 2021; 12(3):732-746. PMC: 8139201. DOI: 10.14336/AD.2020.0523. View

16.

Lui A, Lin F, Uddin A, Nolan B, Clare K, Nguyen T . A double-hit: End-stage renal disease patients suffer worse outcomes in intracerebral hemorrhage. Brain Circ. 2023; 9(3):172-177. PMC: 10679629. DOI: 10.4103/bc.bc_24_23. View

17.

Su M, Zhou Y, Chen Z, Pu M, Li Z, Du H . Cystatin C predicts futile recanalization in patients with acute ischemic stroke after endovascular treatment. J Neurol. 2021; 269(2):966-972. DOI: 10.1007/s00415-021-10680-w. View

18.

Daneman R, Zhou L, Agalliu D, Cahoy J, Kaushal A, Barres B . The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 2010; 5(10):e13741. PMC: 2966423. DOI: 10.1371/journal.pone.0013741. View

19.

Xiao X, Jiang H, Wei H, Zhou Y, Ji X, Zhou C . Endothelial Senescence in Neurological Diseases. Aging Dis. 2023; 14(6):2153-2166. PMC: 10676791. DOI: 10.14336/AD.2023.0226-1. View

20.

Winkler L, Blasig R, Breitkreuz-Korff O, Berndt P, Dithmer S, Helms H . Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke - Ambivalent effects of sealing proteins. J Cereb Blood Flow Metab. 2020; 41(1):132-145. PMC: 7747158. DOI: 10.1177/0271678X20904687. View