Angiopoietin-2 Facilitates Vascular Endothelial Growth Factor-Induced Angiogenesis in the Mature Mouse Brain

Abstract

Background and Purpose— A better understanding of angiogenic factors and their effects on cerebral angiogenesis is necessary for the development of effective therapeutic strategies for ischemic brain injury. Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis in the adult mouse brain. However, the function of angiopoietin-2 (Ang-2) in cerebral angiogenesis has not been clarified. The goal of this study was to identify the combined effects of VEGF and Ang-2 on cerebral angiogenesis and the blood–brain barrier (BBB). Methods— Six groups of 6 adult male CD-1 mice underwent AdlacZ (viral vector control), AdVEGF, AdAng2, VEGF protein, VEGF protein plus AdAng2, or saline (negative control) injection. Microvessels were counted using lectin staining on tissue sections after 2 weeks of treatment. Matrix metalloproteinase-9 (MMP-9) activity was determined by zymography. The presence of zonula occludens-1 (ZO-1) protein was determined by Western blot and immunohistochemistry. Results— Mice treated with VEGF protein infusion plus AdAng-2 significantly increased microvessel counts relative to all other groups ( P <0.05). The changes in MMP-9 activity paralleled the reduced ZO-1 expression in the VEGF plus Ang-2–treated group compared with the other 5 groups ( P <0.05). Double-labeled immunostaining demonstrated that ZO-1–positive staining was significantly decreased on the microvessel wall in the VEGF plus Ang-2–treated group. Conclusions— Our study demonstrates that the combination of VEGF and Ang-2 promotes more angiogenesis compared with VEGF alone. Furthermore, the combination of VEGF and Ang-2 may lead to BBB disruption because it increases MMP-9 activity and inhibits ZO-1 expression.

Exercise Improves Recovery after Ischemic Brain Injury by Inducing the Expression of Angiopoietin-1 and Tie-2 in Rats

“…Ang-2, a natural antagonist of Ang-1, destabilizes the established vasculature, allowing formation of new vessels to occur in the endothelium (Maisonpierre et al 1997;Yuan et al 2009). Also, Ang-2 promotes or inhibits angiogenesis in different micro-environments (Thurston et al 2000;Jones et al 2001;Lobov et al 2002;Zhu et al 2005).…”

“…Ang-2 competitively inhibits the Ang-1/ Tie-2 interaction, leading to disruption of blood vessels (Maisonpierre et al 1997;Asahara et al 1998). Furthermore, Ang-1 and Ang-2 protect the peripheral vasculature from leakage (Thurston et al 1999;Zhu et al 2005;Lee et al 2009), which may account for its anti-edema effects after cerebral ischemia.…”

Angiopoietin-2 is Vasoprotective in the Acute Phase of Cerebral Ischemia

“…Vascular endothelial growth factor is known to limit the expression of such junction proteins. 17,37,38 In parallel to its permeability effect, we observed that VEGF decreases claudin5 and VE-cadherin expression in the ischemic cortices and this effect was abolished in the presence of Ang2. These effects are similar with those reported by Lee et al, 32 who showed that Ang1 counteracts the VEGF-induced increase in vascular permeability by upregulating tight junction protein zonula occludens-2.…”

“…[13][14][15] As an example, both pro-and antipermeability properties have been reported for Ang2 in peripheral tissues as a function of the specific microenvironments. [16][17][18] Furthermore, Ang2 has been described in the brain as an angioneurin, a neologism coined by Zacchigna et al 19 to encompass a particular class of molecules that affects both the vascular and the nervous systems. Paradoxically, although Ang2 is commonly described as an angiogenic factor, data reporting a role for this cytokine in the brain mostly relate to the nervous tissue.…”

Development of blood-brain barrier under the modulation of HIF activity in astroglial and neuronal cells in vitro

“…1А), а также увеличивает продукцию лактата по сравнению с контрольной серией экспериментов (контроль -12,01 нмоль/мкл, FM19G11 -48,38 нмоль/мкл). Увеличение экспрессии VEGF при подавлении активности HIF-1 соответствует данным о том, что в клетках астроглии экспрессия VEGF находится под частичным контролем этого транскрипционного фактора [18].…”