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Angiopoietin1/TIE2 and VEGF/FLK1 Induced by MSC Treatment Amplifies Angiogenesis and Vascular Stabilization after Stroke
Open accessAbstract
Bone marrow stromal cells (MSCs) increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis after stroke. Angiopoietin-1 (Ang1) and its receptor Tie2 mediate vascular integrity and angiogenesis as does VEGF and its receptors. In this study, we tested whether MSC treatment of stroke increases Ang1/Tie2 expression, and whether Ang1/Tie2 with VEGF / vascular endothelial growth factor receptor 2 (VEGFR2) (Flk1), in combination, induced by MSCs enhances angiogenesis and vascular integrity. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAo) and treated with or without MSCs. Marrow stromal cell treatment significantly decreased blood—brain barrier (BBB) leakage and increased Ang1, Tie2, and occludin (a tight junction protein) expression in the ischemic border compared with MCAo control. To further test the mechanisms of MSC-induced angiogenesis and vascular stabilization, cocultures of MSCs with mouse brain endothelial cells (MBECs) or astrocytes were performed. Supernatant derived from MSCs cocultured with MBECs significantly increased MBEC expression of Ang1/Tie2 and Flk1 compared with MBEC alone. Marrow stromal cells cocultured with astrocytes also significantly increased astrocyte VEGF and Ang1/Tie2 expression compared with astrocyte culture alone. Conditioned media from MSCs alone, and media from cocultures of MSCs with astrocytes or MBECs, all significantly increased capillary tube-like formation of MBEC compared with control Dulbecco's modified Eagle's medium media. Inhibition of Flk1 and/or Ang1 significantly decreased MSC-induced MBEC tube formation. Knockdown of Tie2 expression in MBECs significantly inhibited MSC-induced tube formation. Our data indicate MSC treatment of stroke promotes angiogenesis and vascular stabilization, which is at least partially mediated by VEGF/Flk1 and Ang1/Tie2.
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“Subsequent to focal cerebral ischaemia, and in parallel to the downregulation of growth-repulsive proteoglycans, astrocytes de novo express neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF)66 and VEGF,67 and serine proteases, namely tissue plasminogen activator (tPA).68”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [67]
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“Despite the robust evidence for specific time windows in which neuronal plasticity and angiogenesis are most active,64,66,67 neurorestorative treatments were still successful in animals once brain remodelling was induced months after the stroke.18,20”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [67]
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Development, maintenance and disruption of the blood-brain barrier
Obermeier, B., Daneman, R., & Ransohoff, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3407 · Cited by 2,452
Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic
Zhang, Z. G., & Chopp, M. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70061-4 · Cited by 596
Self-citationAstrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke
Liu, Z., & Chopp, M. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.09.008 · Cited by 610
Self-citationBrennan, M. Á., Layrolle, P., & Mooney, D. J. (2020) · Advanced Functional Materials · doi:10.1002/adfm.201909125 · Cited by 399
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Metadata
- Authors
- Zacharek, A., Chen, J., Li, A., Cui, X., Li, Y., Roberts, C., Feng, Y., Gao, Q., & Chopp, M.
- Affiliations
- Henry Ford Health (US)
- Corresponding author
- Chopp, Michael
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2007-10
- Volume
- 27
- Issue
- 10
- Pages
- 1684-1691
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC2796470
- OpenAlex
- W1974547403
- Cited by
- 297
- References
- 36
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 15 · 2023: 10 · 2022: 8 · 2021: 23 · 2020: 13 · 2019: 13 · 2018: 13 · 2017: 27 · 2016: 20 · 2015: 18 · 2014: 21 · 2013: 16 · 2012: 22
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS047682, P01NS23393, P01NS023393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- mesenchymal stem cells, stroke, angiogenesis, angiopoietin-1, Tie2, vascular endothelial growth factor, Flk-1, vascular stabilization, blood-brain barrier disruption, occludin, tight junctions, brain endothelial cells, astrocytes, middle cerebral artery occlusion, capillary tube formation, cell therapy
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Bone Marrow Cells, Cells, Cultured, Gene Expression Regulation, Male, Neovascularization, Pathologic, Stromal Cells, Rats, Wistar, Mice, Knockout, Coculture Techniques, Stroke, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Angiopoietin-1, Endothelial Cells, Receptor, TIE-2, Mice, Rats
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