Angiogenesis

, Volume 21, Issue 2, pp 251–266 | Cite as

Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an α5β1 integrin-mediated mechanism

Original Paper

Abstract

Spinal cord injury (SCI) leads to rapid destruction of neuronal tissue, resulting in devastating motor and sensory deficits. This is exacerbated by damage to spinal cord blood vessels and loss of vascular integrity. Thus, approaches that protect existing blood vessels or stimulate the growth of new blood vessels might present a novel approach to minimize loss or promote regeneration of spinal cord tissue following SCI. In light of the remarkable power of chronic mild hypoxia (CMH) to stimulate vascular remodeling in the brain, the goal of this study was to examine how CMH (8% O2 for up to 7 days) affects blood vessel remodeling in the spinal cord. We found that CMH promoted the following: (1) endothelial proliferation and increased vascularity as a result of angiogenesis and arteriogenesis, (2) increased vascular expression of the angiogenic extracellular matrix protein fibronectin as well as concomitant increases in endothelial expression of the fibronectin receptor α5β1 integrin, (3) strongly upregulated endothelial expression of the tight junction proteins claudin-5, ZO-1 and occludin and (4) astrocyte activation. Of note, the vascular remodeling changes induced by CMH were more extensive in white matter. Interestingly, hypoxic-induced vascular remodeling in spinal cord blood vessels was markedly attenuated in mice lacking endothelial α5 integrin expression (α5-EC-KO mice). Taken together, these studies demonstrate the considerable remodeling potential of spinal cord blood vessels and highlight an important angiogenic role for the α5β1 integrin in promoting endothelial proliferation. They also imply that stimulation of the α5β1 integrin or controlled use of mild hypoxia might provide new approaches for promoting angiogenesis and improving vascular integrity in spinal cord blood vessels.

Keywords

Hypoxia Spinal cord Vascular remodeling Endothelial proliferation Fibronectin Integrin 

Notes

Acknowledgements

This work was supported by the NIH R56 Grant NS095753 (RM). This is Manuscript Number 29533 from The Scripps Research Institute.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

References

  1. 1.
    Hagg T, Oudega M (2006) Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma 23:264–280PubMedGoogle Scholar
  2. 2.
    Oudega M (2010) Spinal cord injury and repair: role of blood vessel loss and endogenous angiogenesis. Adv Wound Care 1:335–340Google Scholar
  3. 3.
    Echeverry S, Shi XQ, Rivest S, Zhang J (2011) Peripheral nerve injury alters blood–spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci 31:10819–10828CrossRefPubMedGoogle Scholar
  4. 4.
    Bramlett HM, Dietrich WD (2007) Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res 161:125–141CrossRefPubMedGoogle Scholar
  5. 5.
    Ek CJ, Habgood MD, Callaway JK, Dennis R, Dziegielewska KM, Johansson PA, Potter A, Wheaton B, Saunders NR (2010) Spatio-temporal progression of grey and white matter damage following contusion injury in rat spinal cord. PLoS ONE 5:e12021CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Fassbender JM, Whittemore SR, Hagg T (2011) Targeting microvasculature for neuroprotection after SCI. Neurotherapeutics 8:240–251CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    LaManna JC, Chavez JC, Pichiule P (2004) Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol 207:3163–3169CrossRefPubMedGoogle Scholar
  8. 8.
    LaManna JC, Vendel LM, Farrell RM (1992) Brain adaptation to chronic hypobaric hypoxia in rats. J Appl Physiol 72:2238–2243CrossRefPubMedGoogle Scholar
  9. 9.
    Milner R, Hung S, Erokwu B, Dore-Duffy P, LaManna JC, del Zoppo GJ (2008) Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia. Mol Cell Neurosci 38:43–52CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Boroujerdi A, Welser-Alves J, Tigges U, Milner R (2012) Chronic cerebral hypoxia promotes arteriogenic remodeling events that can be identified by reduced endoglin (CD105) expression and a switch in β1 integrins. J Cereb Blood Flow Metab 32:1820–1830CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Boroujerdi A, Milner R (2015) Defining the critical hypoxic threshold that promotes vascular remodeling in the brain. Exp Neurol 263:132–140CrossRefPubMedGoogle Scholar
  12. 12.
    Li L, Welser JV, Dore-Duffy P, Del Zoppo GJ, LaManna JC, Milner R (2010) In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the α6β4 integrin and dystroglycan. Glia 58:1157–1167PubMedCentralPubMedGoogle Scholar
  13. 13.
    Chavez JC, Agani F, Pichiule P, LaManna JC (2000) Expression of hypoxic inducible factor 1α in the brain of rats during chronic hypoxia. J Appl Physiol 89:1937–1942CrossRefPubMedGoogle Scholar
  14. 14.
    Kuo N-T, Benhayon D, Przybylski RJ, Martin RJ, LaManna JC (1999) Prolonged hypoxia increases vascular endothelial growth factor mRNA and protein in adult mouse brain. J Appl Physiol 86:260–264CrossRefPubMedGoogle Scholar
  15. 15.
    Pichiule P, LaManna JC (2002) Angiopoietin-2 and rat brain capillary remodeling during adaptation and de-adaptation to prolonged mild hypoxia. J Appl Physiol 93:1131–1139CrossRefPubMedGoogle Scholar
  16. 16.
    Boroujerdi A, Welser-Alves J, Milner R (2013) Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin. Exp Neurol 250:43–51CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Li L, Liu F, Welser-Alves JV, McCullough LD, Milner R (2012) Upregulation of fibronectin and the α5β1 and αvβ3 integrins on blood vessels within the cerebral ischemic penumbra. Exp Neurol 233:283–291CrossRefPubMedGoogle Scholar
  18. 18.
    Li L, Welser-Alves JV, van der Flier A, Boroujerdi A, Hynes RO, Milner R (2012) An angiogenic role for the α5β1 integrin in promoting endothelial cell proliferation during cerebral hypoxia. Exp Neurol 237:46–54CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M (2001) Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol 230:230–242CrossRefPubMedGoogle Scholar
  20. 20.
    van der Flier A, Badu-Nkansah K, Whittaker CA, Crowley D, Roderick T, Bronson DT, Lacy-Hulbert A, Hynes RO (2010) Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development. Development 137:2439–2449CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in α5 integrin-deficient mice. Development 119:1093–1105PubMedGoogle Scholar
  22. 22.
    Milner R, Campbell IL (2002) Developmental regulation of β1 integrins during angiogenesis in the central nervous system. Mol Cell Neurosci 20:616–626CrossRefPubMedGoogle Scholar
  23. 23.
    Hassler O (1966) Blood supply to human spinal cord. A microangiographic study. Arch Neurol 15:302–307CrossRefPubMedGoogle Scholar
  24. 24.
    Turnbull IM, Brieg A, Hassler O (1966) Blood supply of cervical spinal cord in man. A microangiographic cadaver study. J Neurosurg 24:951–965CrossRefPubMedGoogle Scholar
  25. 25.
    Buschmann IR, Busch H-J, Mies G, Hossmann K-A (2003) Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation 108:610–615CrossRefPubMedGoogle Scholar
  26. 26.
    Todo K, Kitagawa K, Sasaki T, Omura-Matsuoka E, Terasaki Y, Oyama N, Yagita Y, Hori M (2008) Granulocyte-macrophage colony-stimulating factor enhances leptomeningeal collateral growth induced by common carotid artery occlusion. Stroke 39:1875–1882CrossRefPubMedGoogle Scholar
  27. 27.
    Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview. Structure, regulation and clinical implications. Neurobiol Dis 16:1–13CrossRefPubMedGoogle Scholar
  28. 28.
    Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neourosci 24:719–725CrossRefGoogle Scholar
  29. 29.
    Wolburg H, Lippoldt A (2002) Tight junctions of the blood–brain barrier; development, composition and regulation. Vasc Pharmacol 38:323–337CrossRefGoogle Scholar
  30. 30.
    Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis—a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci 91:10625–10629CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Fuller DD, Johnson SM, Olson EBJ, Mitchell GS (2003) Synaptic pathways to phrenic motorneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J Neurosci 23:2993–3000PubMedGoogle Scholar
  32. 32.
    Golder FJ, Mitchell GS (2005) Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury. J Neurosci 25:2925–2932CrossRefPubMedGoogle Scholar
  33. 33.
    Gonzalez-Rothi EJ, Lee K-Z, Dale EA, Reier PJ, Mitchell GS, Fuller DD (2015) Intermittent hypoxia and neurorehabilitation. J Appl Physiol 119:1455–1465CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119:1079–1091PubMedGoogle Scholar
  35. 35.
    Taverna D, Hynes RO (2001) Reduced blood vessel formation and tumor growth in alpha5-integrin-negative teratocarcinomas and embryoid bodies. Cancer Res 61:5255–5261PubMedGoogle Scholar
  36. 36.
    Kim S, Bell K, Mousa SA, Varner JA (2000) Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Li L, Welser JV, Milner R (2010) Absence of the αvβ3 integrin dictates the time-course of angiogenesis in the hypoxic central nervous system: accelerated endothelial proliferation correlates with compensatory increases in α5β1 integrin expression. J Cereb Blood Flow Metab 30:1031–1043CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Medicine, MEM-132The Scripps Research InstituteLa JollaUSA

Personalised recommendations