Postischemic Gene Transfer of Soluble Flt-1 Protects against Brain Ischemia with Marked Attenuation of Blood—Brain Barrier Permeability

Abstract

Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or b-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35%), brain edema (by 35%), and blood-brain barrier permeability (Evans blue extravasation; by 69%) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29%) and monocyte/macrophage infiltration (by 27%), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.

Regulations of Astrocytic Functions by Endothelins: Roles in the Pathophysiological Responses of Damaged Brains

“…These findings suggest the involvement of astrocytic ET B receptors in the production of MMPs and VEGF in brain pathologies. Because inhibition of MMPs and VEGF signals prevented the elevated vascular permeability, expressions of these factors are likely pathogenic for vasogenic brain edema (24,25). The production of brain ETs increases in the acute phases of brain insults (3).…”

Bosentan protects the spinal cord from ischemia reperfusion injury in rats through vascular endothelial growth factor receptors

“…23 In addition, inhibition of FLT-1 reduced brain edema after cerebral ischemia in rats, which may be associated with the protection of blood-brain barrier permeability and induction of macrophage/monocyte infiltration. 25 Interestingly, other groups found that FLK-1 and FLT-1 expression increased from day 1 to day 14 following acute spinal cord contusion injury in rats without any treatment. 26 Whereas blocking FLT-1 decreased the infiltration of inflammatory cells, blocking FLK-1 increased neuronal apoptosis and worsened the functional recovery after spinal cord injury, which indicates that FLK-1 plays a crucial neuroprotective role in spinal cord injury.…”

Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy

“…Diabetes causes tremendous edema due to several factors including enhanced protein kinase C activation and higher oxidative stress [68]. Similarly, hypertension is associated with increased vascular endothelial growth (VEGF) and oxidative stress that can increase both hemorrhage and edema [70,71]. Thus, agents on board that inhibit these processes prior to recanalization with ET or IA delivery of these agents during ET (see below) could be effective at preventing reperfusion injury.…”