VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Abstract

After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on bloodbrain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

Hydrogen Sulfide Inhalation Decreases Early Blood—Brain Barrier Permeability and Brain Edema Induced by Cardiac Arrest and Resuscitation

“…In contrast, Ang-1 leads to a decrease in vascular leakage. 15 These results are consistent with our findings in this study. We found that H 2 S inhalation significantly diminished BBB disruption.…”

“…13,14 Angiogenin-1 can counteract VEGF-induced vascular permeability by regulating MMP-9 activity. 15 We evaluated the effects of inhalation of H 2 S gas on neurologic outcome after CA and resuscitation, and examined whether its protective effects were associated with permeability of the BBB. We further examined whether changes in MMP-9, VEGF, and Ang-1 levels were associated with these effects.…”

Buyang Huanwu decoction increases angiopoietin-1 expression and promotes angiogenesis and functional outcome after focal cerebral ischemia

“…It appears to have recruited precursors into the wall of developing vessels, in which the cells are transformed into pericytes and smooth muscle cells. Ang-1 and VEGF in combination induce a synergistic angiogenic effect, and promote the formation of mature neovessels without the side effects on BBB permeability after 7 d (Valable et al, 2005). The coexpression of Ang-1 with VEGF increases the structural integrity of the BBB and reduces atrophy volume at three weeks (Shen et al, 2011).…”

“…Angiopoietin-1 (Ang-1) signaling promotes angiogenesis and remodeling of blood vessels through its receptor tyrosine kinase Tie-2, which is contained in blood vessel endothelial cells. Transgenic overexpression of Ang-1 increases vascular stabilization (Suri et al, 1998;Liu et al, 2012), and Ang-1 and VEGF in combination induce a synergistic angiogenic effect and promote the formation of mature neovessels without the side effects on blood-brain barrier (BBB) permeability (Valable et al, 2005).…”

Post-ischemic Administration of Vascular Endothelial Growth Factor Inhibitor in a Rat Model of Cerebral Venous Infarction

“…Original magnification ×200. induction of matrix metallopeptidase-9 activity, 26) and early increased production of VEGF is deleterious, primarily due to BBB disruption and neuronal cell death. 22) These findings suggest that VEGF can enhance cerebral microvascular perfusion as well as increase BBB leakage in the ischemic brain.…”