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

Abstract

Spinal cord injury (SCI) results in immediate disruption of the spinal vascular network, triggering an ischemic environment and initiating secondary degeneration. Promoting angiogenesis and vascular stability through the induction of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), respectively, provides a possible therapeutic approach in treating SCI. We examined whether supplementing the injured environment with these two factors, which are significantly reduced following injury, has an effect on lesion size and functional outcome. Sustained delivery of both VEGF 165 and Ang-1 was realized using viral vectors based on the adeno-associated virus (AAV), which were injected directly into the lesion epicenter immediately after injury. Our results indicate that the combined treatment with VEGF and Ang-1 resulted in both reduced hyperintense lesion volume and vascular stabilization, as determined by magnetic resonance imaging (MRI). Western blot analysis indicated that the viral vector expression was maintained into the chronic phase of injury, and that the use of the AAV vectors did not exacerbate infiltration of microglia into the lesion epicenter. The combined treatment with AAV-VEGF and AAV-Ang-1 improved locomotor recovery in the chronic phase of injury. These results indicate that combining angiogenesis with vascular stabilization may have potential therapeutic applications following SCI.

Influence of neural stem cell transplantation on angiogenesis in rats with spinal cord injury

“…As a potent angiogenic stimulus and vascular permeability regulation factor (Ferrara et al, 2003), VEGF has been shown to promote angiogenesis after spinal cord injury, and also plays a role in neuroprotection (Widenfalk et al, 2003). Herrera et al (2010) reported that promoting angiogenesis after spinal cord injury improved movement recovery when exogenous VEGF was added. Due to its angiogenic and neuroprotective effects, VEGF may play a supporting role in angiogenic therapy for the spinal cord after injury.…”

Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury

“…Angs are essential for normal vascular functions in the brain [100,101] and spinal cord [102][103][104]. The Ang family has four members: Ang1 through Ang4.…”

“…Ang-2 exerts autocrine and paracrine effects on the Tie-2 receptor, thereby antagonizing the effects of Ang-1. SCI produces a lasting decrease in Ang-1 levels, which further contributes to pronounced vascular dysfunction and functional impairment [103,104]. Contrarily, SCI promotes a marked and persistent increase in Ang-2 levels [106].…”

“…Administration of an αvβ3 integrin-binding peptide (C16) or an Ang-1-mimetic agent following SCI rescued blood vessels at the injury epicenter, prevented white matter degeneration, improved locomotor function, and reduced inflammation [102]. Meanwhile, combined treatment with adenomaassociated virus (AAV)-VEGF and AAV-Ang-1 improved BSCB integrity and functional recovery after SCI [104].…”

Dexmedetomidine Attenuates Blood-Spinal Cord Barrier Disruption Induced by Spinal Cord Ischemia Reperfusion Injury in Rats

“…Ang1 reduces vascular leakage by strengthening PECAM-1 and VE-cadherin regulated interendothelial adhesion [25]. It is also implicated in the pathogenesis of spinal cord injury [26,27]. Ang1 can combat VEGF-induced BSCB breakdown.…”