NeuroMolecular Medicine

, Volume 21, Issue 4, pp 414–431 | Cite as

Oxygen-Glucose Deprivation/Reoxygenation-Induced Barrier Disruption at the Human Blood–Brain Barrier is Partially Mediated Through the HIF-1 Pathway

  • Shyanne Page
  • Snehal Raut
  • Abraham Al-AhmadEmail author
Original Paper


The blood–brain barrier (BBB) plays an important role in brain homeostasis. Hypoxia/ischemia constitutes an important stress factor involved in several neurological disorders by inducing the disruption of the BBB, ultimately leading to cerebral edema formation. Yet, our current understanding of the cellular and molecular mechanisms underlying the BBB disruption following cerebral hypoxia/ischemia remains limited. Stem cell-based models of the human BBB present some potentials to address such issues. Yet, such models have not been validated in regard of its ability to respond to hypoxia/ischemia as existing models. In this study, we investigated the cellular response of two iPSC-derived brain microvascular endothelial cell (BMEC) monolayers to respond to oxygen-glucose deprivation (OGD) stress, using two induced pluripotent stem cells (iPSC) lines. iPSC-derived BMECs responded to prolonged (24 h) and acute (6 h) OGD by showing a decrease in the barrier function and a decrease in tight junction complexes. Such iPSC-derived BMECs responded to OGD stress via a partial activation of the HIF-1 pathway, whereas treatment with anti-angiogenic pharmacological inhibitors (sorafenib, sunitinib) during reoxygenation worsened the barrier function. Taken together, our results suggest such models can respond to hypoxia/ischemia similarly to existing in vitro models and support the possible use of this model as a screening platform for identifying novel drug candidates capable to restore the barrier function following hypoxic/ischemic injury.


Blood–brain barrier Stem cells Cerebral ischemia Hypoxia Reoxygenation 



S.P. and A.A. performed the experiments presented in this study. A.A. designed the study and wrote the manuscript.


This study was funded by TTUHSC institutional funds and by a Laura W. Bush Institute for Women’s Health seed grant to A.A.

Compliance on Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

Supplementary material

12017_2019_8531_MOESM1_ESM.pdf (1.4 mb)
Supplementary Figure 1: Effect of prolonged OGD stress on iPSC-derived neurons and astrocytes. iPSC-derived astrocytes and neurons were incubated in DMEM- for 24 hours. Cells incubated in DMEM+ for 24 hours served as controls. Cell metabolic activity was assessed by measuring changes in MTS in astrocytes (A) and neurons (B) cultures. Secreted VEGF levels in astrocytes (C) and neurons (D) monocultures. Note the higher basal VEGF levels in astrocytes compared to neurons, and the higher VEGF levels in CTR90F-astrocytes compared to CTR65M. (E) Representative micrograph pictures of iPSC-derived neurons following normoxic or prolonged OGD stress. Scale bar = 50µm. (F) Quantitative analysis of neurite cell density. N=3/group, * and ** denote P<0.05 and P<0.01 versus control. Supplementary Figure 2: Mannitol permeability profile in CTR90F and CTR65M monocultures following OGD stress. Changes in mannitol were directly assessed in CTR90F and CTR65M-BMECs after OGD treatment by adding [14C]-mannitol in the apical chamber, whereas sampling occurred for every 15 minutes for 60 minutes. Supplementary Figure 3: Effect of OGD/reoxygenation on astrocytes and neurons. (A) Cell metabolic activity in iPSC-derived astrocytes. Cells were exposed to OGD for 6 hours followed by reoxygenation for 18 hours. (B) HIF-1α protein levels in iPSC-derived astrocytes in normoxic and following 6 hours OGD stress. Note the lower basal expression and the mitigated increase in CTR65M-astrocytes (C) Secreted VEGF levels in iPSC-derived astrocytes in normoxic and OGD stress. (D) Cell metabolic activity in iPSC-derived neurons following OGD/reoxygenation stress. (E) Representative micrograph pictures of iPSC-derived neurons following exposure to OGD and reoxygenation stress. Note the alteration in the quality of neurites, with a severe degradation following reoxygenation stress. Scale bar = 50µm. (F) Quantitative analysis of neurite cell density. N=3/group, * and ** denote P<0.05 and P<0.01 versus control. Supplementary Figure 3: Influence of co-cultures on BMECs response to OGD/reoxygenation stress. iPSC-derived BMECs were co-cultured with their isogenic iPSC-derived astrocytes or neurons for 48 hours prior exposure to OGD/reoxygenation stress. (A) TEER values and (B) fluorescein permeability in BMECs/astrocytes co-cultures. Note the differential outcomes between CTR90F co-cultures versus CTR65M co-cultures. (C and D) TEER and fluorescein permeability values in BMECs/neurons co-cultures. Note the similar outcomes in terms of paracellular permeability in BMECs/neurons co-cultures versus BMECs/astrocytes co-cultures. N=3/group, * and ** denote P<0.05 and P<0.01 versus control. Supplementary material 1 (PDF 1399 KB)
12017_2019_8531_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 12 KB)


  1. Abbruscato, T. J., & Davis, T. P. (1999). Combination of hypoxia/aglycemia compromises in vitro blood-brain barrier integrity. Journal of Pharmacology and Experimental Therapeutics, 289(2), 668–675.PubMedGoogle Scholar
  2. Al Ahmad, A., Gassmann, M., & Ogunshola, O. O. (2009). Maintaining blood-brain barrier integrity: Pericytes perform better than astrocytes during prolonged oxygen deprivation. Journal of Cellular Physiology, 218(3), 612–622. Scholar
  3. Al Ahmad, A., Gassmann, M., & Ogunshola, O. O. (2012). Involvement of oxidative stress in hypoxia-induced blood-brain barrier breakdown. Microvascular Research, 84(2), 222–225. Scholar
  4. Al Ahmad, A., Taboada, C. B., Gassmann, M., & Ogunshola, O. O. (2011). Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. Journal of Cerebral Blood Flow & Metabolism, 31(2), 693–705. Scholar
  5. Al-Ahmad, A. J. (2017). Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells. American Journal of Physiology-Cell Physiology, 313(4), C421–C429. Scholar
  6. Antoniou, X., Gassmann, M., & Ogunshola, O. O. (2011). Cdk5 interacts with Hif-1alpha in neurons: A new hypoxic signalling mechanism? Brain Research, 1381, 1–10. Scholar
  7. Barteczek, P., Li, L., Ernst, A. S., Bohler, L. I., Marti, H. H., & Kunze, R. (2017). Neuronal HIF-1alpha and HIF-2alpha deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke. Journal of Cerebral Blood Flow & Metabolism, 37(1), 291–306. Scholar
  8. Bauer, A. T., Burgers, H. F., Rabie, T., & Marti, H. H. (2010). Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. Journal of Cerebral Blood Flow & Metabolism, 30(4), 837–848. Scholar
  9. Besarab, A., Provenzano, R., Hertel, J., Zabaneh, R., Klaus, S. J., Lee, T., et al. (2015). Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrology Dialysis Transplantation, 30(10), 1665–1673. Scholar
  10. Brillault, J., Berezowski, V., Cecchelli, R., & Dehouck, M. P. (2002). Intercommunications between brain capillary endothelial cells and glial cells increase the transcellular permeability of the blood-brain barrier during ischaemia. Journal of Neurochemistry, 83(4), 807–817.CrossRefGoogle Scholar
  11. Brown, R. C., & Davis, T. P. (2005). Hypoxia/aglycemia alters expression of occludin and actin in brain endothelial cells. Biochemical and Biophysical Research Communications, 327(4), 1114–1123. Scholar
  12. Canfield, S. G., Stebbins, M. J., Morales, B. S., Asai, S. W., Vatine, G. D., Svendsen, C. N., et al. (2017). An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. Journal of Neurochemistry, 140(6), 874–888. Scholar
  13. Chen, Y. F., Lin, Y. C., Chen, J. P., Chan, H. C., Hsu, M. H., Lin, H. Y., et al. (2015). Synthesis and biological evaluation of novel 3,9-substituted beta-carboline derivatives as anticancer agents. Bioorganic & Medicinal Chemistry Letters, 25(18), 3873–3877. Scholar
  14. Chi, O. Z., Hunter, C., Liu, X., & Weiss, H. R. (2008). Effects of deferoxamine on blood-brain barrier disruption and VEGF in focal cerebral ischemia. Neurological Research, 30(3), 288–293. Scholar
  15. Choi, K. H., Kim, H. S., Park, M. S., Kim, J. T., Kim, J. H., Cho, K. A., et al. (2016). Regulation of Caveolin-1 Expression Determines Early Brain Edema After Experimental Focal Cerebral Ischemia. Stroke, 47(5), 1336–1343. Scholar
  16. Chow, J., Ogunshola, O., Fan, S. Y., Li, Y., Ment, L. R., & Madri, J. A. (2001). Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. Brain Research Developmental Brain Research, 130(1), 123–132.CrossRefGoogle Scholar
  17. Chun, Y. S., Yeo, E. J., Choi, E., Teng, C. M., Bae, J. M., Kim, M. S., et al. (2001). Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochemical Pharmacology, 61(8), 947–954.CrossRefGoogle Scholar
  18. Daulatzai, M. A. (2017). Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. Journal of Neuroscience Research, 95(4), 943–972. Scholar
  19. Dore-Duffy, P., Owen, C., Balabanov, R., Murphy, S., Beaumont, T., & Rafols, J. A. (2000). Pericyte migration from the vascular wall in response to traumatic brain injury. Microvascular Research, 60(1), 55–69. Scholar
  20. Drouin-Ouellet, J., Sawiak, S. J., Cisbani, G., Lagace, M., Kuan, W. L., Saint-Pierre, M., et al. (2015). Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: Potential implications for its pathophysiology. Annals of Neurology, 78(2), 160–177. Scholar
  21. Elvidge, G. P., Glenny, L., Appelhoff, R. J., Ratcliffe, P. J., Ragoussis, J., & Gleadle, J. M. (2006). Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: The role of HIF-1alpha, HIF-2alpha, and other pathways. Journal of Biological Chemistry, 281(22), 15215–15226. Scholar
  22. Engelhardt, S., Al-Ahmad, A. J., Gassmann, M., & Ogunshola, O. O. (2014a). Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. Journal of Cellular Physiology, 229(8), 1096–1105. Scholar
  23. Engelhardt, S., Huang, S. F., Patkar, S., Gassmann, M., & Ogunshola, O. O. (2015). Differential responses of blood-brain barrier associated cells to hypoxia and ischemia: A comparative study. Fluids Barriers CNS, 12, 4. Scholar
  24. Engelhardt, S., Patkar, S., & Ogunshola, O. O. (2014b). Cell-specific blood-brain barrier regulation in health and disease: A focus on hypoxia. British Journal of Pharmacology, 171(5), 1210–1230. Scholar
  25. Feng, S., Cen, J., Huang, Y., Shen, H., Yao, L., Wang, Y., et al. (2011). Matrix metalloproteinase-2 and – 9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS ONE, 6(8), e20599. Scholar
  26. Fernandez-Lopez, D., Faustino, J., Daneman, R., Zhou, L., Lee, S. Y., Derugin, N., et al. (2012). Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. The Journal of Neuroscience, 32(28), 9588–9600. Scholar
  27. Fischer, S., Clauss, M., Wiesnet, M., Renz, D., Schaper, W., & Karliczek, G. F. (1999). Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. American Journal of Physiology, 276(4 Pt 1), C812–C820.CrossRefGoogle Scholar
  28. Fischer, S., Wiesnet, M., Marti, H. H., Renz, D., & Schaper, W. (2004). Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells. Journal of Cellular Physiology, 198(3), 359–369. Scholar
  29. Fischer, S., Wobben, M., Marti, H. H., Renz, D., & Schaper, W. (2002). Hypoxia-induced hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula occludens-1. Microvascular Research, 63(1), 70–80. Scholar
  30. Freeze, W. M., Bacskai, B. J., Frosch, M. P., Jacobs, H. I. L., Backes, W. H., Greenberg, S. M., et al. (2019). Blood-Brain Barrier Leakage and Microvascular Lesions in Cerebral Amyloid Angiopathy. Stroke, 50(2), 328–335. Scholar
  31. Genetos, D. C., Cheung, W. K., Decaris, M. L., & Leach, J. K. (2010). Oxygen tension modulates neurite outgrowth in PC12 cells through a mechanism involving HIF and VEGF. Journal of Molecular Neuroscience, 40(3), 360–366. Scholar
  32. Ghiso, J., Fossati, S., & Rostagno, A. (2014). Amyloidosis associated with cerebral amyloid angiopathy: Cell signaling pathways elicited in cerebral endothelial cells. Journal of Alzheimer’s Disease, 42(Suppl 3), 167–176. Scholar
  33. Greenberg, D. A., & Jin, K. (2013). Vascular endothelial growth factors (VEGFs) and stroke. Cellular and Molecular Life Sciences, 70(10), 1753–1761. Scholar
  34. Gussenhoven, R., Klein, L., Ophelders, D., Habets, D. H. J., Giebel, B., Kramer, B. W., et al. (2019). Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy. Clinical Medicine, 8(2), Scholar
  35. Haarmann, A., Deiss, A., Prochaska, J., Foerch, C., Weksler, B., Romero, I., et al. (2010). Evaluation of soluble junctional adhesion molecule-A as a biomarker of human brain endothelial barrier breakdown. PLoS ONE, 5(10), e13568. Scholar
  36. Hackett, P. H., & Roach, R. C. (2004). High altitude cerebral edema. High Altitude Medicine & Biology, 5(2), 136–146. Scholar
  37. Haley, M. J., & Lawrence, C. B. (2017). The blood-brain barrier after stroke: Structural studies and the role of transcytotic vesicles. Journal of Cerebral Blood Flow & Metabolism, 37(2), 456–470. Scholar
  38. Helms, H. C., Abbott, N. J., Burek, M., Cecchelli, R., Couraud, P. O., Deli, M. A., et al. (2016). In vitro models of the blood-brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use. Journal of Cerebral Blood Flow & Metabolism, 36(5), 862–890. Scholar
  39. Holloway, P. M., & Gavins, F. N. (2016). Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives. Stroke, 47(2), 561–569. Scholar
  40. Jang, S., Zheng, C., Tsai, H. T., Fu, A. Z., Barac, A., Atkins, M. B., et al. (2016). Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. Cancer, 122(1), 124–130. Scholar
  41. Jin, K., Zhu, Y., Sun, Y., Mao, X. O., Xie, L., & Greenberg, D. A. (2002). Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proceedings of the National Academy of Sciences of the USA, 99(18), 11946–11950. Scholar
  42. Jin, X., Sun, Y., Xu, J., & Liu, W. (2015). Caveolin-1 mediates tissue plasminogen activator-induced MMP-9 up-regulation in cultured brain microvascular endothelial cells. Journal of Neurochemistry, 132(6), 724–730. Scholar
  43. Kanazawa, M., Igarashi, H., Kawamura, K., Takahashi, T., Kakita, A., Takahashi, H., et al. (2011). Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment. Journal of Cerebral Blood Flow & Metabolism, 31(6), 1461–1474. Scholar
  44. Kassner, A., & Merali, Z. (2015). Assessment of Blood-Brain Barrier Disruption in Stroke. Stroke, 46(11), 3310–3315. Scholar
  45. Ke, X. J., & Zhang, J. J. (2013). Changes in HIF-1alpha, VEGF, NGF and BDNF levels in cerebrospinal fluid and their relationship with cognitive impairment in patients with cerebral infarction. Journal of Huazhong University of Science and Technology Medical Sciences, 33(3), 433–437. Scholar
  46. Kilic, E., Kilic, U., Wang, Y., Bassetti, C. L., Marti, H. H., & Hermann, D. M. (2006). The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF’s neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB Journal, 20(8), 1185–1187. Scholar
  47. Kim, E., Yang, J., Park, K. W., & Cho, S. (2018). Inhibition of VEGF Signaling Reduces Diabetes-Exacerbated Brain Swelling, but Not Infarct Size, in Large Cerebral Infarction in Mice. Translational Stroke Research, 9(5), 540–548. Scholar
  48. Kim, H., Lee, J. M., Park, J. S., Jo, S. A., Kim, Y. O., Kim, C. W., et al. (2008). Dexamethasone coordinately regulates angiopoietin-1 and VEGF: A mechanism of glucocorticoid-induced stabilization of blood-brain barrier. Biochemical and Biophysical Research Communications, 372(1), 243–248. Scholar
  49. Kim, K. A., Shin, D., Kim, J. H., Shin, Y. J., Rajanikant, G. K., Majid, A., et al. (2018). Role of Autophagy in Endothelial Damage and Blood-Brain Barrier Disruption in Ischemic Stroke. Stroke, 49(6), 1571–1579. Scholar
  50. Kokubu, Y., Yamaguchi, T., & Kawabata, K. (2017). In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells. Biochemical and Biophysical Research Communications, 486(2), 577–583. Scholar
  51. Koto, T., Takubo, K., Ishida, S., Shinoda, H., Inoue, M., Tsubota, K., et al. (2007). Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells. The American Journal of Pathology, 170(4), 1389–1397. Scholar
  52. Kuntz, M., Mysiorek, C., Petrault, O., Petrault, M., Uzbekov, R., Bordet, R., et al. (2014). Stroke-induced brain parenchymal injury drives blood-brain barrier early leakage kinetics: A combined in vivo/in vitro study. Journal of Cerebral Blood Flow & Metabolism, 34(1), 95–107. Scholar
  53. Lafuente, J. V., Bermudez, G., Camargo-Arce, L., & Bulnes, S. (2016). Blood-Brain Barrier Changes in High Altitude. CNS Neurological Disorders - Drug Targets, 15(9), 1188–1197.CrossRefGoogle Scholar
  54. Lee, C. A. A., Seo, H. S., Armien, A. G., Bates, F. S., Tolar, J., & Azarin, S. M. (2018). Modeling and rescue of defective blood-brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients. Fluids Barriers CNS, 15(1), 9. Scholar
  55. Lee, K., Lee, J. H., Boovanahalli, S. K., Jin, Y., Lee, M., Jin, X., et al. (2007). Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors. Journal of Medicinal Chemistry, 50(7), 1675–1684. Scholar
  56. Lee, W. L. A., Michael-Titus, A. T., & Shah, D. K. (2017). Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates. Developmental Neuroscience, 39(1–4), 49–58. Scholar
  57. Lim, R. G., Quan, C., Reyes-Ortiz, A. M., Lutz, S. E., Kedaigle, A. J., Gipson, T. A., et al. (2017). Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits. Cell Reports, 19(7), 1365–1377. Scholar
  58. Lin, L., Chen, H., Zhang, Y., Lin, W., Liu, Y., Li, T., et al. (2015). IL-10 Protects Neurites in Oxygen-Glucose-Deprived Cortical Neurons through the PI3K/Akt Pathway. PLoS ONE, 10(9), e0136959. Scholar
  59. Lippmann, E. S., Al-Ahmad, A., Azarin, S. M., Palecek, S. P., & Shusta, E. V. (2014). A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Scientific Reports, 4, 4160. Scholar
  60. Liu, J., Jin, X., Liu, K. J., & Liu, W. (2012). Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. The Journal of Neuroscience, 32(9), 3044–3057. Scholar
  61. Liu, W., Hendren, J., Qin, X. J., Shen, J., & Liu, K. J. (2009). Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. Journal of Neurochemistry, 108(3), 811–820. Scholar
  62. Lochhead, J. J., McCaffrey, G., Quigley, C. E., Finch, J., DeMarco, K. M., Nametz, N., et al. (2010). Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. Journal of Cerebral Blood Flow & Metabolism, 30(9), 1625–1636. Scholar
  63. Lopez-Iglesias, P., Alcaina, Y., Tapia, N., Sabour, D., Arauzo-Bravo, M. J., de la Maza, S., D., et al (2015). Hypoxia induces pluripotency in primordial germ cells by HIF1alpha stabilization and Oct4 deregulation. Antioxid Redox Signal, 22(3), 205–223. Scholar
  64. Lu, D., Mai, H. C., Liang, Y. B., Xu, B. D., Xu, A. D., & Zhang, Y. S. (2018). Beneficial Role of Rosuvastatin in Blood-Brain Barrier Damage Following Experimental Ischemic Stroke. Frontiers in Pharmacology, 9, 926. Scholar
  65. Ma, Q., Dasgupta, C., Li, Y., Huang, L., & Zhang, L. (2017). MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury. International Journal of Molecular Sciences. 18(7), Scholar
  66. Mani, N., Khaibullina, A., Krum, J. M., & Rosenstein, J. M. (2005). Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: Receptor mediation and signal transduction pathways. Experimental Neurology, 192(2), 394–406. Scholar
  67. Mani, N., Khaibullina, A., Krum, J. M., & Rosenstein, J. M. (2010). Vascular endothelial growth factor enhances migration of astroglial cells in subventricular zone neurosphere cultures. Journal of Neuroscience Research, 88(2), 248–257. Scholar
  68. Margaritescu, O., Pirici, D., & Margaritescu, C. (2011). VEGF expression in human brain tissue after acute ischemic stroke. Romanian Journal of Morphology and Embryology, 52(4), 1283–1292. doi:52041112831292 [pii].PubMedGoogle Scholar
  69. Mark, K. S., & Davis, T. P. (2002). Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. American Journal of Physiology-Heart and Circulatory Physiology, 282(4), H1485–H1494. Scholar
  70. Martin-Aragon Baudel, M. A. S., Rae, M. T., Darlison, M. G., Poole, A. V., & Fraser, J. A. (2017). Preferential activation of HIF-2alpha adaptive signalling in neuronal-like cells in response to acute hypoxia. PLoS ONE, 12(10), e0185664. Scholar
  71. Mathieu, J., Zhou, W., Xing, Y., Sperber, H., Ferreccio, A., Agoston, Z., et al. (2014). Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell, 14(5), 592–605. Scholar
  72. McCaffrey, G., Willis, C. L., Staatz, W. D., Nametz, N., Quigley, C. A., Hom, S., et al. (2009). Occludin oligomeric assemblies at tight junctions of the blood-brain barrier are altered by hypoxia and reoxygenation stress. Journal of Neurochemistry, 110(1), 58–71. Scholar
  73. Medley, T. L., Furtado, M., Lam, N. T., Idrizi, R., Williams, D., Verma, P. J., et al. (2013). Effect of oxygen on cardiac differentiation in mouse iPS cells: Role of hypoxia inducible factor-1 and Wnt/beta-catenin signaling. PLoS ONE, 8(11), e80280. Scholar
  74. Merali, Z., Huang, K., Mikulis, D., Silver, F., & Kassner, A. (2017). Evolution of blood-brain-barrier permeability after acute ischemic stroke. PLoS ONE, 12(2), e0171558. Scholar
  75. Mimeault, M., & Batra, S. K. (2013). Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine, 17(1), 30–54. Scholar
  76. Mo, S. J., Hong, J., Chen, X., Han, F., Ni, Y., Zheng, Y., et al. (2016). VEGF-mediated NF-kappaB activation protects PC12 cells from damage induced by hypoxia. Neuroscience Letters, 610, 54–59. Scholar
  77. Na, J. I., Na, J. Y., Choi, W. Y., Lee, M. C., Park, M. S., Choi, K. H., et al. (2015). The HIF-1 inhibitor YC-1 decreases reactive astrocyte formation in a rodent ischemia model. American Journal of Translational Research, 7(4), 751–760.PubMedPubMedCentralGoogle Scholar
  78. Naik, P., & Cucullo, L. (2012). In vitro blood-brain barrier models: Current and perspective technologies. Journal of Pharmaceutical Sciences, 101(4), 1337–1354. Scholar
  79. Nakashima, Y., Miyagi-Shiohira, C., Noguchi, H., & Omasa, T. (2018). Atorvastatin Inhibits the HIF1alpha-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells. Molecular Therapy, 26(7), 1715–1734. Scholar
  80. Natah, S. S., Srinivasan, S., Pittman, Q., Zhao, Z., & Dunn, J. F. (2009). Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats. Journal of Applied Physiology (1985), 107(4), 1348–1356. Scholar
  81. Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D’Orazio, L. M., Pachicano, M., et al. (2019). Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine. Scholar
  82. Neuwelt, E. A., Bauer, B., Fahlke, C., Fricker, G., Iadecola, C., Janigro, D., et al. (2011). Engaging neuroscience to advance translational research in brain barrier biology. Nature Reviews Neuroscience, 12(3), 169–182. Scholar
  83. Nobes, C. D., Hay, W. W. Jr., & Brand, M. D. (1990). The mechanism of stimulation of respiration by fatty acids in isolated hepatocytes. Journal of Biological Chemistry, 265(22), 12910–12915.PubMedGoogle Scholar
  84. O’Donnell, M. E. (2014). Blood-brain barrier Na transporters in ischemic stroke. Advances in Pharmacology, 71, 113–146. Scholar
  85. Ogunshola, O. O. (2011). In vitro modeling of the blood-brain barrier: Simplicity versus complexity. Current Pharmaceutical Design, 17(26), 2755–2761. doi:BSP/CPD/E-Pub/000559 [pii].CrossRefGoogle Scholar
  86. Ogunshola, O. O., & Al-Ahmad, A. (2012). HIF-1 at the blood-brain barrier: A mediator of permeability? High Altitude Medicine & Biology, 13(3), 153–161. Scholar
  87. Ohab, J. J., Fleming, S., Blesch, A., & Carmichael, S. T. (2006). A neurovascular niche for neurogenesis after stroke. The Journal of Neuroscience, 26(50), 13007–13016. Scholar
  88. Orchard, P. J., Nascene, D. R., Miller, W. P., Gupta, A., Kenney-Jung, D., & Lund, T. C. (2019). Successful donor engraftment and repair of the blood brain barrier in cerebral adrenoleukodystrophy. Blood. Scholar
  89. Page, S., Munsell, A., & Al-Ahmad, A. J. (2016). Cerebral hypoxia/ischemia selectively disrupts tight junctions complexes in stem cell-derived human brain microvascular endothelial cells. Fluids Barriers CNS, 13(1), 16. Scholar
  90. Palmiotti, C. A., Prasad, S., Naik, P., Abul, K. M., Sajja, R. K., Achyuta, A. H., et al. (2014). In vitro cerebrovascular modeling in the 21st century: Current and prospective technologies. Pharmaceutical Research, 31(12), 3229–3250. Scholar
  91. Patel, R., Page, S., & Al-Ahmad, A. J. (2017). Isogenic blood-brain barrier models based on patient-derived stem cells display inter-individual differences in cell maturation and functionality. Journal of Neurochemistry, 142(1), 74–88. Scholar
  92. Perriere, N., Demeuse, P., Garcia, E., Regina, A., Debray, M., Andreux, J. P., et al. (2005). Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. Journal of Neurochemistry, 93(2), 279–289. Scholar
  93. Pikula, A., Beiser, A. S., Chen, T. C., Preis, S. R., Vorgias, D., DeCarli, C., et al. (2013). Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study. Stroke, 44(10), 2768–2775. Scholar
  94. Plaschke, K., Staub, J., Ernst, E., & Marti, H. H. (2008). VEGF overexpression improves mice cognitive abilities after unilateral common carotid artery occlusion. Experimental Neurology, 214(2), 285–292. Scholar
  95. Prakash, R., & Carmichael, S. T. (2015). Blood-brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury. Current Opinion in Neurology, 28(6), 556–564. Scholar
  96. Roskoski, R. Jr. (2017). Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacological Research, 120, 116–132. Scholar
  97. Ruan, L., Wang, B., ZhuGe, Q., & Jin, K. (2015). Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Research, 1623, 166–173. Scholar
  98. Sajja, R. K., Prasad, S., & Cucullo, L. (2014). Impact of altered glycaemia on blood-brain barrier endothelium: An in vitro study using the hCMEC/D3 cell line. Fluids Barriers CNS, 11(1), 8. Scholar
  99. Schmid-Brunclik, N., Burgi-Taboada, C., Antoniou, X., Gassmann, M., & Ogunshola, O. O. (2008). Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 295(3), R864–R873. Scholar
  100. Schoch, H. J., Fischer, S., & Marti, H. H. (2002). Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain, 125(Pt 11), 2549–2557.CrossRefGoogle Scholar
  101. Suzuki, Y., Nagai, N., & Umemura, K. (2016). A Review of the Mechanisms of Blood-Brain Barrier Permeability by Tissue-Type Plasminogen Activator Treatment for Cerebral Ischemia. Frontiers in Cellular Neuroscience, 10, 2. Scholar
  102. Sweeney, M. D., Montagne, A., Sagare, A. P., Nation, D. A., Schneider, L. S., Chui, H. C., et al. (2019). Vascular dysfunction-The disregarded partner of Alzheimer’s disease. Alzheimers Dementia, 15(1), 158–167. Scholar
  103. Turner, R. J., & Sharp, F. R. (2016). Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. Frontiers in Cellular Neuroscience, 10, 56. Scholar
  104. Vatine, G. D., Al-Ahmad, A., Barriga, B. K., Svendsen, S., Salim, A., Garcia, L., et al. (2017). Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier. Cell Stem Cell, 20(6), 831–843 e835. Scholar
  105. Vogel, C., Bauer, A., Wiesnet, M., Preissner, K. T., Schaper, W., Marti, H. H., et al. (2007). Flt-1, but not Flk-1 mediates hyperpermeability through activation of the PI3-K/Akt pathway. Journal of Cellular Physiology, 212(1), 236–243. Scholar
  106. Wang, Q., Yang, L., & Wang, Y. (2015). Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen-glucose deprivation. International Journal of Developmental Neuroscience, 43, 50–57. Scholar
  107. Wang, R., Zhang, X., Zhang, J., Fan, Y., Shen, Y., Hu, W., et al. (2012). Oxygen-glucose deprivation induced glial scar-like change in astrocytes. PLoS ONE, 7(5), e37574. Scholar
  108. Wang, Y., Jin, K., Mao, X. O., Xie, L., Banwait, S., Marti, H. H., et al. (2007). VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. Journal of Neuroscience Research, 85(4), 740–747. Scholar
  109. Wang, Y., Sang, A., Zhu, M., Zhang, G., Guan, H., Ji, M., et al. (2016). Tissue factor induces VEGF expression via activation of the Wnt/beta-catenin signaling pathway in ARPE-19 cells. Molecular Vision, 22, 886–897.PubMedPubMedCentralGoogle Scholar
  110. Wang, Z. G., Cheng, Y., Yu, X. C., Ye, L. B., Xia, Q. H., Johnson, N. R., et al. (2016). bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury. Molecular Neurobiology, 53(10), 7298–7311. Scholar
  111. Weksler, B. B., Subileau, E. A., Perriere, N., Charneau, P., Holloway, K., Leveque, M., et al. (2005). Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB Journal, 19(13), 1872–1874. Scholar
  112. Witt, K. A., Mark, K. S., Hom, S., & Davis, T. P. (2003). Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. American Journal of Physiology-Heart and Circulatory Physiology, 285(6), H2820–H2831. Scholar
  113. Wu, C., Chen, J., Chen, C., Wang, W., Wen, L., Gao, K., et al. (2015). Wnt/beta-catenin coupled with HIF-1alpha/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia. Scientific Reports, 5, 16151. Scholar
  114. Wu, F., Chen, Z., Tang, C., Zhang, J., Cheng, L., Zuo, H., et al. (2017). Acid fibroblast growth factor preserves blood-brain barrier integrity by activating the PI3K-Akt-Rac1 pathway and inhibiting RhoA following traumatic brain injury. American Journal of Translational Research, 9(3), 910–925.PubMedPubMedCentralGoogle Scholar
  115. Yan, J., Zhang, Z., & Shi, H. (2012). HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cellular and Molecular Life Sciences, 69(1), 115–128. Scholar
  116. Yan, J., Zhou, B., Taheri, S., & Shi, H. (2011). Differential effects of HIF-1 inhibition by YC-1 on the overall outcome and blood-brain barrier damage in a rat model of ischemic stroke. PLoS ONE, 6(11), e27798. Scholar
  117. Yang, T., Roder, K. E., & Abbruscato, T. J. (2007). Evaluation of bEnd5 cell line as an in vitro model for the blood-brain barrier under normal and hypoxic/aglycemic conditions. Journal of Pharmaceutical Sciences, 96(12), 3196–3213. Scholar
  118. Yang, Y., & Rosenberg, G. A. (2011). Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke, 42(11), 3323–3328. Scholar
  119. Yang, Y., Thompson, J. F., Taheri, S., Salayandia, V. M., McAvoy, T. A., Hill, J. W., et al. (2013). Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. Journal of Cerebral Blood Flow & Metabolism, 33(7), 1104–1114. Scholar
  120. Yeh, W. L., Lu, D. Y., Lin, C. J., Liou, H. C., & Fu, W. M. (2007). Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Molecular Pharmacology, 72(2), 440–449. Scholar
  121. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920. Scholar
  122. Zhang, Q. L., Cui, B. R., Li, H. Y., Li, P., Hong, L., Liu, L. P., et al. (2013). MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria. Biochemical and Biophysical Research Communications, 438(3), 507–512. Scholar
  123. Zhang, S., An, Q., Wang, T., Gao, S., & Zhou, G. (2018). Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood-Brain Barrier Permeability During Early Reperfusion in Stroke. Neuroscience, 377, 126–137. Scholar
  124. Zhang, Z., Yan, J., & Shi, H. (2016). Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke. Neurobiology of Disease, 95, 82–92. Scholar
  125. Zhang, Z. G., Zhang, L., Jiang, Q., Zhang, R., Davies, K., Powers, C., et al. (2000). VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. Journal of Clinical Investigation, 106(7), 829–838. Scholar
  126. Zhong, J., Chan, A., Morad, L., Kornblum, H. I., Fan, G., & Carmichael, S. T. (2010). Hydrogel matrix to support stem cell survival after brain transplantation in stroke. Neurorehabilitation and Neural Repair, 24(7), 636–644. Scholar
  127. Zhu, H., Wang, Z., Xing, Y., Gao, Y., Ma, T., Lou, L., et al. (2012). Baicalin reduces the permeability of the blood-brain barrier during hypoxia in vitro by increasing the expression of tight junction proteins in brain microvascular endothelial cells. Journal of Ethnopharmacology, 141(2), 714–720. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA

Personalised recommendations