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Open Access 01-12-2024 | Research

β1 integrins play a critical role maintaining vascular integrity in the hypoxic spinal cord, particularly in white matter

Authors: Sebok K. Halder, Arjun Sapkota, Richard Milner

Published in: Acta Neuropathologica Communications | Issue 1/2024

Abstract

Interactions between extracellular matrix (ECM) proteins and β1 integrins play an essential role maintaining vascular integrity in the brain, particularly under vascular remodeling conditions. As blood vessels in the spinal cord are reported to have distinct properties from those in the brain, here we examined the impact of β1 integrin inhibition on spinal cord vascular integrity, both under normoxic conditions, when blood vessels are stable, and during exposure to chronic mild hypoxia (CMH), when extensive vascular remodeling occurs. We found that a function-blocking β1 integrin antibody triggered a small degree of vascular disruption in the spinal cord under normoxic conditions, but under hypoxic conditions, it greatly enhanced (20-fold) vascular disruption, preferentially in spinal cord white matter (WM). This resulted in elevated microglial activation as well as marked loss of myelin integrity and reduced density of oligodendroglial cells. To understand why vascular breakdown is localized to WM, we compared expression levels of major BBB components of WM and grey matter (GM) blood vessels, but this revealed no obvious differences. Interestingly however, hypoxyprobe staining demonstrated that the most severe levels of spinal cord hypoxia induced by CMH occurred in the WM. Analysis of brain tissue revealed a similar preferential vulnerability of WM tracts to show vascular disruption under these conditions. Taken together, these findings demonstrate an essential role for β1 integrins in maintaining vascular integrity in the spinal cord, and unexpectedly, reveal a novel and fundamental difference between WM and GM blood vessels in their dependence on β1 integrin function during hypoxic exposure. Our data support the concept that the preferential WM vulnerability described may be less a result of intrinsic differences in vascular barrier properties between WM and GM, and more a consequence of differences in vascular density and architecture.

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Arteel GE, Thurman RG, Yates JM, Raleigh JA (1995) Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72:889–895. https://doi.org/10.1038/bjc.1995.429CrossRefPubMedPubMedCentral

Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview. Structure, regulation and clinical implications. Neurobiol Dis 16:1–13CrossRefPubMed

Boroujerdi A, Welser-Alves J, Milner R (2015) Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5. Angiogenesis 18:255–264CrossRefPubMed

Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566CrossRefPubMedPubMedCentral

Daniel PM, Lam DK, Pratt OE (1985) Comparison of the vascular permeability of the brain and the spinal cord to mannitol and inulin in rats. J Neurochem 45:647–649. https://doi.org/10.1111/j.1471-4159.1985.tb04038.xCrossRefPubMed

Davies DC (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646CrossRefPubMedPubMedCentral

Davis GE, Senger DR (2008) Extracellular matrix mediates a molecular balance between vascular morphogenesis and regression. Curr Opin Hematol 15:197–203. https://doi.org/10.1097/MOH.0b013e3282fcc321CrossRefPubMed

del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26:1966–1975CrossRefPubMed

Eliceiri BP, Cheresh D (2001) Adhesion events in angiogenesis. Curr Opin Cell Biol 13:563–568CrossRefPubMed

10.

Fantini S, Sassaroli A, Tgavalekos KT, Kornbluth J (2016) Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. Neurophotonics 3:031411. https://doi.org/10.1117/1.NPh.3.3.031411CrossRefPubMedPubMedCentral

11.

Gay D, Esiri M (1991) Blood-brain barrier damage in Acute multiple sclerosis plaques. Brain 114:557–572CrossRefPubMed

12.

Ge S, Pachter JS (2006) Isolation and culture of microvascular endothelial cells from murine spinal cord. J Neuroimmunol 177:209–214. https://doi.org/10.1016/j.jneuroim.2006.05.012CrossRefPubMed

13.

Halder SK, Milner R (2019) A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord. Proc Natl Acad Sci U S A 116:26029–26037CrossRefPubMedPubMedCentral

14.

Halder SK, Milner R (2020) Mild hypoxia triggers transient blood-brain barrier disruption: a fundamental protective role for microglia. Acta Neuropathol Commun 8:175. https://doi.org/10.1186/s40478-020-01051-zCrossRefPubMedPubMedCentral

15.

Halder SK, Milner R (2022) Exaggerated hypoxic vascular breakdown in aged brain due to reduced microglial vasculo-protection. Aging Cell: e13720. https://doi.org/10.1111/acel.13720CrossRef

16.

Halder SK, Milner R (2023) Spinal cord blood vessels in aged mice show greater levels of Hypoxia-Induced Vascular disruption and microglial activation. Int J Mol Sci 24. https://doi.org/10.3390/ijms241411235

17.

Halder SK, Kant R, Milner R (2018) Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an a5β1 integrin-mediated mechanism. Angiogenesis 21:251–266CrossRefPubMedPubMedCentral

18.

Halder SK, Delorme-Walker VD, Milner R (2023) β1 integrin is essential for blood-brain barrier integrity under stable and vascular remodelling conditions; effects differ with age. Fluids Barriers CNS 20:52. https://doi.org/10.1186/s12987-023-00453-0CrossRefPubMedPubMedCentral

19.

Hassler O (1966) Blood supply to human spinal cord. A microangiographic study. Arch Neurol 15:302–307CrossRefPubMed

20.

Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neourosci 24:719–725CrossRef

21.

Hynes RO (1987) Integrins: a family of cell surface receptors. Cell 48:549–554CrossRefPubMed

22.

Izawa Y, Gu YH, Osada T, Kanazawa M, Hawkins BT, Koziol JA, Papayannopoulou T, Spatz M, Del Zoppo GJ (2018) β1-integrin-matrix interactions modulate cerebral microvessel endothelial cell tight junction expression and permeability. J Cereb Blood Flow Metab 38:641–658. https://doi.org/10.1177/0271678x17722108CrossRefPubMed

23.

LaManna JC, Vendel LM, Farrell RM (1992) Brain adaptation to chronic hypobaric hypoxia in rats. J Appl Physiol 72:2238–2243CrossRefPubMed

24.

Li X, Sarkar SN, Purdy DE, Briggs RW (2014) Quantifying cerebellum grey matter and white matter perfusion using pulsed arterial spin labeling. Biomed Res Int 2014(108691). https://doi.org/10.1155/2014/108691

25.

Milner R, Campbell IL (2002) Developmental regulation of β1 integrins during angiogenesis in the central nervous system. Mol Cell Neurosci 20:616–626CrossRefPubMed

26.

Osada T, Gu Y-H, Kanazawa M, Tsubota Y, Hawkins BT, Spatz M, Milner R, del Zoppo GJ (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by β1 integrins. J Cereb Blood Flow Metab 31:1972–1985CrossRefPubMedPubMedCentral

27.

Oudega M (2010) Spinal cord injury and repair: role of blood vessel loss and endogenous angiogenesis. Adv Wound Care 1:335–340

28.

Pan W, Banks WA, Kastin AJ (1997) Blood-brain barrier permeability to ebiratide and TNF in acute spinal cord injury. Exp Neurol 146:367–373. https://doi.org/10.1006/exnr.1997.6533CrossRefPubMed

29.

Pan W, Banks WA, Kastin AJ (1997) Permeability of the blood-brain and blood-spinal cord barriers to interferons. J Neuroimmunol 76:105–111 Doi 10.1016/s0165-5728(97)00034– 9CrossRefPubMed

30.

Petersen MA, Ryu JK, Chang KJ, Etxeberria A, Bardehle S, Mendiola AS, Kamau-Devers W, Fancy SPJ, Thor A, Bushong EA al (2017) Fibrinogen activates BMP Signaling in Oligodendrocyte Progenitor cells and inhibits remyelination after vascular damage. Neuron 96:1003–1012e1007. https://doi.org/10.1016/j.neuron.2017.10.008CrossRefPubMedPubMedCentral

31.

Prockop LD, Naidu KA, Binard JE, Ransohoff J (1995) Selective permeability of [3H]-D-mannitol and [14 C]-carboxyl-inulin across the blood-brain barrier and blood-spinal cord barrier in the rabbit. J Spinal Cord Med 18:221–226. https://doi.org/10.1080/10790268.1995.11719399CrossRefPubMed

32.

Raleigh JA, Calkins-Adams DP, Rinker LH, Ballenger CA, Weissler MC, Fowler WC Jr., Novotny DB, Varia MA (1998) Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res 58:3765–3768PubMed

33.

Stromblad S, Cheresh DA (1996) Integrins, angiogenesis and vascular cell survival. Chem Biol 3:881–885CrossRefPubMed

34.

Turnbull IM, Brieg A, Hassler O (1966) Blood supply of cervical spinal cord in man. A microangiographic cadaver study. J Neurosurg 24:951–965CrossRefPubMed

35.

Waters S, Swanson MEV, Dieriks BV, Zhang YB, Grimsey NL, Murray HC, Turner C, Waldvogel HJ, Faull RLM An J (2021) blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS. Acta Neuropathol Commun 9: 144 https://doi.org/10.1186/s40478-021-01244-0

36.

Winkler EA, Sengillo JD, Bell RD, Wang J, Zlokovic BV (2012) Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J Cereb Blood Flow Metab 32:1841–1852. https://doi.org/10.1038/jcbfm.2012.113CrossRefPubMedPubMedCentral

37.

Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JHet al et al (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111:E1035–1042. https://doi.org/10.1073/pnas.1401595111CrossRefPubMedPubMedCentral

38.

Wolburg-Burcholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, Wolburg H (2006) Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol 118:219–233CrossRef

39.

Yamamoto H, Ehling M, Kato K, Kanai K, van Lessen M, Frye M, Zeuschner D, Nakayama M, Vestweber D, Adams RH (2015) Integrin β1 controls VE-cadherin localization and blood vessel stability. Nat Commun 6:6429. https://doi.org/10.1038/ncomms7429CrossRefPubMed

Title: β1 integrins play a critical role maintaining vascular integrity in the hypoxic spinal cord, particularly in white matter
Authors: Sebok K. Halder
Arjun Sapkota
Richard Milner
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-024-01749-4

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β1 integrins play a critical role maintaining vascular integrity in the hypoxic spinal cord, particularly in white matter

Abstract

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