Summary
A better understanding of angiogenic factors and their effects on angiogenesis in brain is necessary to treat cerebral vascular disorders such as ischemic brain injury. Vascular endothelial growth factor (VEGF) induces angiogenesis and increases blood-brain barrier (BBB) permeability in adult mouse brain. The effect of angiopoietin-1 on BBB leakage during the angiogenesis process is unclear. We sought to identify the effects of combining VEGF with angiopoietin-1 on cerebral angiogenesis and BBB.
Adult male CD-1 mice underwent AdFc (adenoviral vector control), AdAng-1, VEGF protein, VEGF protein plus AdAng-1, or saline (negative control) injection. Brain microvessels were counted using lectin staining on tissue sections after 2 weeks of adenoviral gene transfer. The presence of zonula occludens-1 (ZO-1) was determined by Western blot analysis and immunohistochemistry.
Microvessel count and augmented capillary diameter increased in mice treated with either VEGF protein or AdAng-1 plus VEGF protein compared to saline, AdFc, or AdAng-1 alone (p < 0.05). Double-labeled immunostaining demonstrated that ZO-1-positive staining was more complete on the microvessel wall in the AdAng-1 and AdAng-1 plus VEGF protein treated group compared to VEGF protein group. The results of ZO-1 expression from Western blot analysis paralleled that from immunohistochemistry (p < 0.05).
We conclude that focal VEGF and angiopoietin-1 hyperstimulation in mouse brain increases microvessel density while maintaining ZO-1 protein expression, suggesting that angiopoietin-1 plays a role in synergistically inducing angiogenesis and BBB integrity.
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References
Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274: 23463–23467
Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD, Isner JM (1998) Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res 83: 233–240
Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49: 507–521
Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5: 1359–1364
Fischer S, Wobben M, Marti HH, Renz D, Schaper W (2002) Hypoxia-induced hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula occludens-1. Microvasc Res 63: 70–80
Gentil BJ, Benaud C, Delphin C, Remy C, Berezowski V, Cecchelli R, Feraud O, Vittet D, Baudier J (2005) Specific AHNAK expression in brain endothelial cells with barrier properties. J Cell Physiol 203: 362–371
Harrigan MR, Ennis SR, Masada T, Keep RF (2002) Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 50: 589–598
Iizasa H, Bae SH, Asashima T, Kitano T, Matsunaga N, Terasaki T, Kang YS, Nakashima E (2002) Augmented expression of the tight junction protein occludin in brain endothelial cell line TR-BBB by rat angiopoietin-1 expressed in baculovirus-infected Sf plus insect cells. Pharm Res 19: 1757–1760
Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2: 257–267
Lee CZ, Xu B, Hashimoto T, McCulloch CE, Yang GY, Young WL (2004) Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model. Stroke 35: 1715–1719
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadoupoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277: 55–60
Rieckmann P, Engelhardt B (2003) Building up the blood-brain barrier. Nat Med 9: 828–829
Song L, Pachter JS (2004) Monocyte chemoattractant protein-1 alters expression of tight junction-associated proteins in brain microvascular endothelial cells. Microvasc Res 67: 78–89
Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6: 460–463
Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, Young WL, Yang GY (2004) Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab 24: 237–244
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407: 242–248
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Zhu, Y. et al. (2006). Effects of angiopoietin-1 on vascular endothelial growth factor-induced angiogenesis in the mouse brain. In: Hoff, J.T., Keep, R.F., Xi, G., Hua, Y. (eds) Brain Edema XIII. Acta Neurochirurgica Supplementum, vol 96. Springer, Vienna. https://doi.org/10.1007/3-211-30714-1_90
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DOI: https://doi.org/10.1007/3-211-30714-1_90
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