Yıl: 2022 Cilt: 59 Sayı: Ek 1 Sayfa Aralığı: 29 - 35 Metin Dili: Türkçe DOI: 10.29399/npa.28171 İndeks Tarihi: 08-05-2023

Serebral İskemi Patofizyolojisinde Perisitlerin Önemi

Öz:
Serebral iskeminin beyinde yarattığı değişikliklerde çeşitli hücre tipleri görev almaktadır. Perisitler nörovasküler ünitede yer alan, uzun yıllar ihmal edilmiş, tanımlanmasında ve literatürde çelişkili sonuçların çıkmasına neden olmuş bir hücre tipidir. Hem literatürde hem de yaptığımız çalışmalarla perisitlerin kasılıp gevşeyerek serebral kan akımını özellikle kapiller düzeyde kontrol edebildiği, KBB’nin gelişimini ve idamesini sağladığı, beyin damarlarının gelişiminde ve yeni damar oluşumunda hem yol gösterici olduğu hem de yeni damarları stabilize ettiği ortaya konmuştur. Aynı zamanda uyaranlara cevap olarak inflamasyona katkıda bulunma ve multipotent farklılaşma özelliği göstererek farklı hücre tiplerine dönüşebilme gibi farklı fonksiyonları olduğu da gösterilmiştir. Serebral dolaşımla yakından ilişkili bu hücre tipi serebral iskemi durumunda da önemli roller oynamaktadır. Bu derlemede perisitlerin özellikleri ve fizyolojik fonksiyonlarından kısaca bahsedilerek, iskemi durumunda nasıl değiştikleri, iskemik inme ve inme sonrası kognitif bozukluk patofizyolojisindeki rolleri tartışılacaktır. Perisitlerin güncel metodlarla açık bir şekilde karakterize edilmesi bu hücrelerin iskemi patofizyolojisinde oynadığı rolleri daha iyi anlamada yardımcı olacaktır. Bu şekilde elde edilecek bilgilerle spesifik olarak perisit hedefli tedaviler geliştirmek ve iskemik inme tedavisinde bu hücrelerin potansiyelini kullanarak klinik iyileşmede önemli ilerlemeler sağlamak mümkün olacaktır.
Anahtar Kelime:

Importance of Pericytes in the Pathophysiology of Cerebral Ischemia

Öz:
Various cell types contribute to pathological changes observed in the brain following cerebral ischemia. Pericytes, as a component of neurovascular unit (NVU) and blood brain barrier (BBB), play a key role for cerebral blood flow control and regulation of vessel permeability. It was shown that pericytes can control cerebral blood flow at the level of capillaries, by their contractile property. Their role in BBB development and maintenance are crucial for guidance of brain vessel development, new vessel formation and stabilization of the newly formed vessels. Additionally, they can contribute to inflammation in response to inflammatory stimuli and can differentiate to various cell types by their multipotent differentiation properties. This cell type which is intimately associated with cerebral circulation also plays important roles during cerebral ischemia. Here, we review the properties and physiological functions of pericytes, how these functions change during ischemia to affect the pathophysiology of ischemic stroke and post stroke cognitive impairment. Pericytes are a neglected cell type and they are not unambiguously characterized which in turn led to contradictory findings in the literature. Clear characterization of pericytes by current methods will help better understanding of their role in the pathophysiology of stroke. With the information gained from these efforts it will be possible to develop pericyte specific therapeutic targets and achieve important breakthroughs in clinical recovery in ischemic stroke treatment.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık
  • 1. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795–820. [Crossref]
  • 2. Gautam J, Yao Y. Roles of pericytes in stroke pathogenesis. Cell Transplant. 2018;27(12):1798–1808. [Crossref]
  • 3. Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215. [Crossref]
  • 4. Alarcon-Martinez L, Yilmaz-Ozcan S, Yemisci M, Schallek J, Kilic K, Can A ve ark. Capillary pericytes express alpha-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. Elife. 2018;7:e34861. [Crossref]
  • 5. Hartmann DA, Berthiaume A-A, Grant RI, Harrill SA, Koski T, Tieu T ve ark. Brain capillary pericytes exert a substantial but slow influence on blood flow. Nature Neurosci. 2021;24(5):633–645. [Crossref]
  • 6. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab. 2016;36(2):451–455. [Crossref]
  • 7. Hartmann D, Underly R, Grant R, Watson A, Lindner V, Shih A. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics. 2015;2(4):041402. [Crossref]
  • 8. Alarcon-Martinez L, Yemisci M, Dalkara T. Pericyte morphology and function. Histol Histopathol. 2021;36(6):633–643. [Crossref]
  • 9. Hartmann DA, Coelho-Santos V, Shih AY. Pericyte control of blood flow across microvascular zones in the central nervous system. Annu Rev Physiol. 2022;84(1):331–354. [Crossref]
  • 10. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA ve ark. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508(7494):55–60. [Crossref]
  • 11. Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron. 2015;87(1):95–110. [Crossref]
  • 12. Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 2017;18(7):419–434. [Crossref]
  • 13. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R ve ark. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68(3):409–427. [Crossref]
  • 14. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for bloodbrain barrier integrity during embryogenesis. Nature. 2010;468(7323):562– 566. [Crossref]
  • 15. Sun Z, Gao C, Gao D, Sun R, Li W, Wang F ve ark. Reduction in pericyte coverage leads to blood-brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion. Fluids Barriers CNS. 2021;18(1):21. [Crossref]
  • 16. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C ve ark. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557–561. [Crossref]
  • 17. Vazquez-Liebanas E, Nahar K, Bertuzzi G, Keller A, Betsholtz C, Mae MA. Adult-induced genetic ablation distinguishes PDGFB roles in bloodbrain barrier maintenance and development. J Cereb Blood Flow Metab. 2022;42(2):264–279. [Crossref]
  • 18. Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev. 2004;15(4):215–228. [Crossref] 19. Ribatti D, Nico B, Crivellato E. The role of pericytes in angiogenesis. Int J Dev Biol. 2011;55(3):261–268. [Crossref]
  • 20. Caporarello N, D’Angeli F, Cambria MT, Candido S, Giallongo C, Salmeri M ve ark. Pericytes in microvessels: from “mural” function to brain and retina regeneration. Int J Mol Sci. 2019;20(24). [Crossref]
  • 21. Locatelli M, Padovani A, Pezzini A. Pathophysiological mechanisms and potential therapeutic targets in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Front Pharmacol. 2020;11:321. [Crossref]
  • 22. Rustenhoven J, Jansson D, Smyth LC, Dragunow M. Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci. 2017;38(3):291– 304. [Crossref]
  • 23. Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain. J Neurochem. 2010;115(5):1077–1089. [Crossref]
  • 24. Proebstl D, Voisin M-B, Woodfin A, Whiteford J, D’Acquisto F, Jones GE ve ark. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J Exp Med. 2012;209(6):1219–1234. [Crossref]
  • 25. Cai W, Liu H, Zhao J, Chen LY, Chen J, Lu Z ve ark. Pericytes in brain injury and repair after ischemic stroke. Transl Stroke Res. 2017;8(2):107–121. [Crossref]
  • 26. Nakagomi T, Kubo S, Nakano-Doi A, Sakuma R, Lu S, Narita A ve ark. Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. Stem Cells. 2015;33(6):1962–1974. [Crossref]
  • 27. Nakata M, Nakagomi T, Maeda M, Nakano-Doi A, Momota Y, Matsuyama T. Induction of perivascular neural stem cells and possible contribution to neurogenesis following transient brain ischemia/reperfusion injury. Transl Stroke Res. 2017;8(2):131–143. [Crossref]
  • 28. Tong L, Hill RA, Damisah EC, Murray KN, Yuan P, Bordey A ve ark. Imaging and optogenetic modulation of vascular mural cells in the live brain. Nat Protoc. 2021;16(1):472–496. [Crossref]
  • 29. Vanlandewijck M, He L, Mae MA, Andrae J, Ando K, Del Gaudio F ve ark. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–480. [Crossref]
  • 30. Campisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. 2018;180:117–129. [Crossref]
  • 31. Dore-Duffy P, Esen N. The microvascular pericyte: approaches to isolation, characterization, and cultivation. Adv Exp Med Biol. 2018;1109:53–65. [Crossref]
  • 32. Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009;15(9):1031–1037. [Crossref]
  • 33. El Amki M, Gluck C, Binder N, Middleham W, Wyss MT, Weiss T ve ark. Neutrophils obstructing brain capillaries are a major cause of no-reflow in ischemic stroke. Cell Rep. 2020;33(2):108260. [Crossref]
  • 34. Gürler G, Soylu KO, Yemişci M. The mysterious phenomenon of ischemic stroke: no-reflow. Türk Beyin Damar Hast Derg. 2021;27(3):179–190. [Crossref]
  • 35. Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J ve ark. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron. 2014;82(3):603–617. [Crossref]
  • 36. Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des. 2012;18(25):3653–3662. [Crossref]
  • 37. Hatakeyama M, Ninomiya I, Kanazawa M. Angiogenesis and neuronal remodeling after ischemic stroke. Neural Regen Res. 2020;15(1):16–19. [Crossref]
  • 38. Nakamura K, Arimura K, Nishimura A, Tachibana M, Yoshikawa Y, Makihara N ve ark. Possible involvement of basic FGF in the upregulation of PDGFRβ in pericytes after ischemic stroke. Brain Res. 2016;1630:98–108. [Crossref]
  • 39. Arimura K, Ago T, Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J ve ark. PDGF receptor beta signaling in pericytes following ischemic brain injury. Curr Neurovasc Res. 2012;9(1):1–9. [Crossref]
  • 40. Beck H, Plate KH. Angiogenesis after cerebral ischemia. Acta Neuropathol. 2009;117(5):481–496. [Crossref]
  • 41. Gong C-X, Zhang Q, Xiong X-Y, Yuan J-J, Yang G-Q, Huang J-C ve ark. Pericytes regulate cerebral perfusion through VEGFR1 in ischemic stroke. Cell Mol Neurobiol. 2021. [Crossref]
  • 42. Kokovay E, Li L, Cunningham LA. Angiogenic recruitment of pericytes from bone marrow after stroke. J Cereb Blood Flow Metab. 2006;26(4):545–555. [Crossref]
  • 43. Nih LR, Deroide N, Leré-Déan C, Lerouet D, Soustrat M, Levy BI ve ark. Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell coadministration. Eur J Neurosci. 2012;35(8):1208–1217. [Crossref]
  • 44. Özen I, Deierborg T, Miharada K, Padel T, Englund E, Genové G ve ark. Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol. 2014;128(3):381–396. [Crossref]
  • 45. Sakuma R, Kawahara M, Nakano-Doi A, Takahashi A, Tanaka Y, Narita A ve ark. Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. J Neuroinflammation. 2016;13(1):57. [Crossref]
  • 46. Tatebayashi K, Tanaka Y, Nakano-Doi A, Sakuma R, Kamachi S, Shirakawa M ve ark. Identification of multipotent stem cells in human brain tissue following stroke. Stem Cells Dev. 2017;26(11):787–797. [Crossref]
  • 47. Nakagomi T, Takagi T, Beppu M, Yoshimura S, Matsuyama T. Neural regeneration by regionally induced stem cells within post-stroke brains: Novel therapy perspectives for stroke patients. World J Stem Cells. 2019;11(8):452–463. [Crossref]
  • 48. Mijajlović MD, Pavlović A, Brainin M, Heiss W-D, Quinn TJ, Ihle-Hansen HB ve ark. Post-stroke dementia - a comprehensive review. BMC Med. 2017;15(1):11. [Crossref]
  • 49. Uemura MT, Maki T, Ihara M, Lee VM, Trojanowski JQ. Brain microvascular pericytes in vascular cognitive impairment and dementia. Front Aging Neurosci. 2020;12:80. [Crossref]
  • 50. Ding R, Hase Y, Ameen-Ali KE, Ndung’u M, Stevenson W, Barsby J ve ark. Loss of capillary pericytes and the blood-brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease. Brain Pathol. 2020;30(6):1087–1101. [Crossref]
  • 51. Ding R, Hase Y, Burke M, Foster V, Stevenson W, Polvikoski T ve ark. Loss with ageing but preservation of frontal cortical capillary pericytes in post-stroke dementia, vascular dementia and Alzheimer’s disease. Acta Neuropathol Commun. 2021;9(1):130. [Crossref]
  • 52. Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D ve ark. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med. 2018;24(3):326–337. [Crossref]
  • 53. Guimaraes-Camboa N, Cattaneo P, Sun Y, Moore-Morris T, Gu Y, Dalton ND ve ark. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell. 2017;20(3):345–359.e5. [Crossref]
  • 54. Sun J, Huang Y, Gong J, Wang J, Fan Y, Cai J ve ark. Transplantation of hPSCderived pericyte-like cells promotes functional recovery in ischemic stroke mice. Nat Commun. 2020;11(1):5196. [Crossref]
  • 55. Shen J, Xu G, Zhu R, Yuan J, Ishii Y, Hamashima T ve ark. PDGFR-beta restores blood-brain barrier functions in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2019;39(8):1501–1515. [Crossref]
  • 56. Paul G, Zachrisson O, Varrone A, Almqvist P, Jerling M, Lind G ve ark. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients. J Clin Invest. 2015;125(3):1339–1346. [Crossref]
  • 57. LeBlanc NJ, Guruswamy R, ElAli A. Vascular endothelial growth factor isoform-B stimulates neurovascular repair after ischemic stroke by promoting the function of pericytes via vascular endothelial growth factor receptor-1. Mol Neurobiol. 2018;55(5):3611–3626. [Crossref]
  • 58. Omote Y, Deguchi K, Kono S, Liu N, Liu W, Kurata T ve ark. Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation. J Neurosci Res. 2014;92(3):369–374. [Crossref]
  • 59. Takeshita T, Nakagawa S, Tatsumi R, So G, Hayashi K, Tanaka K ve ark. Cilostazol attenuates ischemia-reperfusion-induced blood-brain barrier dysfunction enhanced by advanced glycation endproducts via transforming growth factor-beta1 signaling. Mol Cell Neurosci. 2014;60:1–9. [Crossref]
  • 60. Dias DO, Kalkitsas J, Kelahmetoglu Y, Estrada CP, Tatarishvili J, Holl D ve ark. Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions. Nat Commun. 2021;12(1):5501. [Crossref]
  • 61. Gaudin A, Yemisci M, Eroglu H, Lepetre-Mouelhi S, Turkoglu OF, DönmezDemir B ve ark. Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury. Nat Nanotechnol. 2014;9(12):1054–1062. [Crossref]
  • 62. Kang E, Shin JW. Pericyte-targeting drug delivery and tissue engineering. Int J Nanomedicine. 2016;11:2397–2406. [Crossref]
  • 63. He L, Vanlandewijck M, Raschperger E, Mae MA, Jung B, Lebouvier T ve ark. Analysis of the brain mural cell transcriptome. Sci Rep. 2016;6:35108. [Crossref]
APA Gurler G, Soylu K, Yemisci M (2022). Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. , 29 - 35. 10.29399/npa.28171
Chicago Gurler Gokce,Soylu Kadir Oguzhan,Yemisci Muge Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. (2022): 29 - 35. 10.29399/npa.28171
MLA Gurler Gokce,Soylu Kadir Oguzhan,Yemisci Muge Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. , 2022, ss.29 - 35. 10.29399/npa.28171
AMA Gurler G,Soylu K,Yemisci M Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. . 2022; 29 - 35. 10.29399/npa.28171
Vancouver Gurler G,Soylu K,Yemisci M Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. . 2022; 29 - 35. 10.29399/npa.28171
IEEE Gurler G,Soylu K,Yemisci M "Serebral İskemi Patofizyolojisinde Perisitlerin Önemi." , ss.29 - 35, 2022. 10.29399/npa.28171
ISNAD Gurler, Gokce vd. "Serebral İskemi Patofizyolojisinde Perisitlerin Önemi". (2022), 29-35. https://doi.org/10.29399/npa.28171
APA Gurler G, Soylu K, Yemisci M (2022). Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. Nöropsikiyatri Arşivi, 59(Ek 1), 29 - 35. 10.29399/npa.28171
Chicago Gurler Gokce,Soylu Kadir Oguzhan,Yemisci Muge Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. Nöropsikiyatri Arşivi 59, no.Ek 1 (2022): 29 - 35. 10.29399/npa.28171
MLA Gurler Gokce,Soylu Kadir Oguzhan,Yemisci Muge Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. Nöropsikiyatri Arşivi, vol.59, no.Ek 1, 2022, ss.29 - 35. 10.29399/npa.28171
AMA Gurler G,Soylu K,Yemisci M Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. Nöropsikiyatri Arşivi. 2022; 59(Ek 1): 29 - 35. 10.29399/npa.28171
Vancouver Gurler G,Soylu K,Yemisci M Serebral İskemi Patofizyolojisinde Perisitlerin Önemi. Nöropsikiyatri Arşivi. 2022; 59(Ek 1): 29 - 35. 10.29399/npa.28171
IEEE Gurler G,Soylu K,Yemisci M "Serebral İskemi Patofizyolojisinde Perisitlerin Önemi." Nöropsikiyatri Arşivi, 59, ss.29 - 35, 2022. 10.29399/npa.28171
ISNAD Gurler, Gokce vd. "Serebral İskemi Patofizyolojisinde Perisitlerin Önemi". Nöropsikiyatri Arşivi 59/Ek 1 (2022), 29-35. https://doi.org/10.29399/npa.28171