Neuroprotection of Ischemic Brain by Vascular Endothelial Growth Factor is Critically Dependent on Proper Dosage and May Be Compromised by Angiogenesis

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O 2 ) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with a-fluoromethylhistidine (a-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or a-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.

Section: Discussionsupporting

confidence: 54%

Activation of the Central Histaminergic System is Involved in Hypoxia-Induced Stroke Tolerance in Adult Mice

Fan

Dai

et al. 2010

“…Neurons with pale nucleus and cytoplasm were considered viable neurons. Viable neurons with nucleolus were counted using a modified correction factor to adjust for partial profiles (Manoonkitiwongsa et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Friedman

Cheng

et al. 2007

The role of angiogenesis after stroke is unclear; if angiogenesis supports long-term recovery of blood flow, then microvessel hyperdensity consequent to angiogenesis should persist in infarcted cortex. Here, we assess the long-term stability of ischemia-induced microvessels after 2-h transient rat middle cerebral artery occlusion (tMCAo) followed by 30, 90, or 165 days of reperfusion. Stereological measures of microvessel density were taken adjacent to and within cortical cysts. Vascular permeability was documented by extravasation of immunoglobulin (IgG) and of fluorescein-dextran. After 30 days reperfusion, a significantly increased microvessel volume density (V V ) was restricted to the inner margin of cystic infarcts as compared with the region external to the infarct or contralateral control cortex (F = 42.675, P < 0.001). The hyperdense ischemic vasculature was abnormally leaky to IgG and fluorescein-dextran. Between 30 and 90 days of reperfusion, this vessel hyperdensity regressed significantly and then regressed further but less drastically between 90 and 165 days. Phagocytic macrophages were restricted to the infarct and dynamic changes in their number correlated with microvessel regression. Additional ED-1 labeled inflammatory cells were widely distributed inside and external to the infarct, even after 165 days of reperfusion. These data show that ischemia evoked angiogenesis results, at least in part, in transient populations of leaky microvessels and phagocytic macrophages. This suggests that a major role of this angiogenesis is for the removal of necrotic brain tissue.

“…Based on the above data and on our findings, a novel therapeutic approach based on an early administration of both angiogenic factors leading to a limitation of the extent of neuronal death might be encouraged for the treatment of cerebral ischemia. However, it has been shown that neuroprotection and angiogenesis induced by VEGF monotherapy do not necessarily occur at the same dose of exogenous VEGF (Manoonkitiwongsa et al, 2004). Consequently, it would be necessarily, in the future, to investigate the role of endogenous VEGF and Ang-1 and to determine whether an optimal parenchymal concentration of both agents can safely stimulate both angiogenesis and neuroprotection in relation with an increase in functional outcome (Hori et al, 2004;Iizasa et al, 2002;Wang et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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

Valable

Montaner

Bellail

et al. 2005

177

125

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.