Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2

Abstract

Abstract. Brain microvessels possess barrier structures comprising tight junctions which are critical for the maintenance of central nervous system homeostasis. Brain vascular diseases, such as ischemic stroke damage to blood-brain barrier, increase the vascular permeability, and then lead to vasogenic brain edema. Herein, we examined whether angiopoietin-1 (Ang-1) could regulate zonula occludens-2 (ZO-2) expression and counteract vascular endothelial growth factor (VEGF)-induced vascular permeability. When we treated brain microvascular endothelial cells with Ang-1, Ang-1 caused a time-and dosedependent increase of ZO-2 and down-regulation in endothelial permeability. VEGF, one of the key regulators of ischemiainduced vascular permeability, increased endothelial cell permeability in vitro, whereas, Ang-1 reversed this VEGF effect by up-regulating ZO-2 expression. Additionally, the recovery effect of Ang-1 on permeability was strongly blocked by siRNA against ZO-2. Collectively, our results suggest that Ang-1 shows anti-permeability activity through up-regulation of ZO-2.

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

“…The permeabilizing effect of VEGF has been described in several models of cerebral ischemia and is counteracted by Ang1. 8,32,33 An unexpected and interesting finding in our study is that our data resemble those obtained for Ang1, despite the fact that Ang1 and Ang2 are usually described as agonists and antagonists in angiogenesis. Indeed, if Ang1 is known to stabilize blood vessels in the brain as well as in peripheral tissues, Ang2 is normally thought to be a factor that favors vascular permeability.…”

Sustained Expression of Vascular Endothelial Growth Factor and Angiopoietin-1 Improves Blood–Spinal Cord Barrier Integrity and Functional Recovery after Spinal Cord Injury

“…The reduction in the general compromise of the BSCB as indicated by the decrease in the percentage of enhanced area seen on contrast MRI might denote a re-establishment of the tight junction network. A recent publication by Lee and colleagues demonstrated that in vitro, Ang-1 reduces VEGF-induced brain microvessel permeability by upregulating the tight junction protein zonula occludens-2 (Lee et al, 2009). In addition, occludin, a transmembrane protein expressed exclusively at the tight junction complexes, is induced by Ang-1 expression in brain capillary endothelial cells (Hori et al, 2004).…”

Angiopoietin-1 Protects Heart against Ischemia/Reperfusion Injury through VE-Cadherin Dephosphorylation and Myocardiac Integrin-β1/ERK/Caspase-9 Phosphorylation Cascade

“…Angiopoietin-1 (Ang-1) is a strong antipermeability factor that binds to the endothelial-specific Tie2 receptor and induces Tie2 phosphorylation (6,7). Ang-1/ Tie2 signaling regulates vessel formation and maintenance of endothelial integrity (8,9).…”