VEGF Protects Brain against Focal Ischemia without Increasing Blood–Brain Permeability When Administered Intracerebroventricularly

Abstract

Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood-brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently of the decrease in infarct size, VEGF also reduced the number of TUNEL-positive apoptotic neurons. Phospo-Akt levels were significantly higher in ischemic hemispheres of the VEGF-treated mice. Contrary to intracerebroventricular route, intravenous administration of VEGF (15 microg/kg) enhanced the infarct volume as previously reported for the rat. In conclusion, single intracerebroventricular injection of VEGF protects brain against ischemia without adversely affecting BBB permeability, and has a relatively long therapeutic time window. This early neuroprotective action, observed well before recovery-promoting actions such as angiogenesis, possibly involves activation of the PI-3-Akt pathway.

Bone marrow stromal cell transplantation through tail vein injection promotes angiogenesis and vascular endothelial growth factor expression in cerebral infarct area in rats

“…Besides angiogenesis, intracerebroventricular injection of VEGF protects the brain against ischemia [22]. This early neuroprotective action progresses before angiogenesis, possibly through activation of the phosphoinositol-3-kinase (PI3K-Akt) pathway [22]. VEGF also protects HN33 mouse hippocampal neuron X neuroblastoma cells from death induced by serum withdrawal [26] and reduces hypoxic death of both HN33 cells and cultured cerebral cortical neurons [39,40].…”

“…VEGF-A can stimulate the release of endothelial progenitor cells from bone marrow to facilitate angiogenesis after infarction [11]. Besides angiogenesis, intracerebroventricular injection of VEGF protects the brain against ischemia [22]. This early neuroprotective action progresses before angiogenesis, possibly through activation of the phosphoinositol-3-kinase (PI3K-Akt) pathway [22].…”

“…VEGF also promotes the formation of new cerebral blood vessels [19,20]. Introduction of VEGF to the surface of the brain reduces infarct size [21]; intravenous VEGF improves neurological function [18]; intracerebroventricular injection of VEGF protects the brain against ischemia [22]. Furthermore, intraventricular injection of anti-VEGF antibody increases infarct size after focal cerebral ischemia [23].…”

Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential

“…For example, a combination of VEGF and angiopoietin 2 was necessary for promoting the growth of vascular sprouts in mature mouse brain [95]. The method of administration seems to be important as only intracerebroventricularly administered VEGF protected the brain against focal ischaemia [107]. In addition VEGFR (VEGF receptor)-1 (also known as Flt-1) induces MMPs [108], as does PDGFR signalling (see above).…”

“…Combination therapy would not only need to secure 'safe' angiogenesis, but also to stimulate neurogenesis [14]. VEGF has been demonstrated to have an early neuroprotective action [115] observed significantly before recovery-promoting actions, such as angiogenesis, and possibly involving activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway [107]. Hypoxia-induced PlGF, a ligand for VEGFR-1 and neuropilin-1, is involved in co-ordinated regulation of angiogenesis and neurogenesis after stroke [116].…”