Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO

Abstract

In this study, an in vitro model of the blood-brain barrier, consisting of porcine brain-derived microvascular endothelial cells (BMEC), was used to evaluate the mechanism of hypoxia-induced hyperpermeability. We show that hypoxia-induced permeability in BMEC was completely abolished by a neutralizing antibody to vascular endothelial growth factor (VEGF). In contrast, under normoxic conditions, addition of VEGF up to 100 ng/ml did not alter monolayer barrier function. Treatment with either hypoxia or VEGF under normoxic conditions induced a twofold increase in VEGF binding sites and VEGF receptor 1 (Flt-1) mRNA expression in BMEC. Hypoxia-induced permeability also was prevented by the nitric oxide (NO) synthase inhibitor N G-monomethyl-l-arginine, suggesting that NO is involved in hypoxia-induced permeability changes, which was confirmed by measurements of the cGMP level. During normoxia, treatment with VEGF (5 ng/ml) increased permeability as well as cGMP content in the presence of several antioxidants. These results suggest that hypoxia-induced permeability in vitro is mediated by the VEGF/VEGF receptor system in an autocrine manner and is essentially dependent on reducing conditions stabilizing the second messenger NO as the mediator of changes in barrier function of BMEC.

Nanoparticle transport across the blood brain barrier

“…The effect of hypoxia-ischemia on the BBB has been extensively investigated 57 ; Bolton et al, 1998; 34,65 : this disease sets in motion a series of events, which leads to disruption of TJ and increased BBB permeability, probably mediated by cytokines, VEGF, and NO. Moreover, elevated levels of proinflammatory cytokines, IL-1b, and TNF-a have been demonstrated in animal brains after focal and global ischemia 33 and in cerebrospinal fluid of stroke patients.…”

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

“…59 All events that initate this increased permeability have not been completely defined, but VEGF expression by neoplastic cells is a known cause of increased vascular leakage. 60,61 The end result is that plasma coagulation factors enter tissue spaces where they are activated, leading to the formation of a fibrin plug and platelet aggregation.…”

Effect of intracortical vascular endothelial growth factor infusion and blockade during the critical period in the rat visual cortex

“…As has been pointed out before, VEGF mediates vascular permeability, inducing a leakage of the BBB in some pathological situations (Fischer et al, 1999;van Bruggen et al, 1999;Schoch et al, 2002;Nordal and Wong, 2005). In addition, VEGF is a potent activator of astroglial response (Krum et al, 2002).…”