Angiogenesis, neurogenesis and brain recovery of function following injury

Abstract

Stroke and traumatic brain injury (TBI) are major causes of mortality and morbidity worldwide. Unfortunately, almost all phase III clinical trials of neuroprotective agents for stroke and TBI have demonstrated no benefit, raising concerns regarding the use of neuroprotective strategies alone as therapy for acute brain injuries. Therefore, a compelling need exists to develop treatments that promote both the repair and regeneration of injured brain tissue, and functional recovery. Recent data suggest that strategies to enhance neurogenesis and angiogenesis following brain injuries may provide promising opportunities to improve clinical outcomes and brain functional recovery. This review discusses neurogenesis and angiogenesis in the adult brain following stroke or TBI. Selected cell-based and pharmacological therapies are highlighted that promote neurogenesis and angiogenesis and are designed to restore neurological function after brain injuries. These discoveries emphasize the need for an improved understanding of injury- and therapy-induced neurogenesis and angiogenesis in the adult brain, and suggest that the manipulation of endogenous neural precursors and endothelial cells is a potential therapy for brain injury.

Figure 1. A simplified schematic diagram summarizing injury- and therapy-induced angiogenesis and neurogenesis after TBI and stroke

Following brain injury, CXC-chemokine receptor-4 (CXCR4)-expressing subventricular zone (SVZ) neuroblasts are attracted by increased stromal-derived factor 1 (SDF-1)α to migrate into the lesion boundary zone, where they differentiate into neural cells. Similarly, mesenchymal stem cells (MSCs) and endothelial precursor cells (EPCs) are directed to injured brain regions, where they secret growth factors to promote angiogenesis and neurogenesis. Erythropoietin (EPO) and statins promote the migration of SVZ neuroblasts into injured brain regions. Treatment with EPO/carbamylated erythropoietin (CEPO), statins, PDE5 inhibitors, MSCs, VEGF or basic FGF increases angiogenesis and neurogenesis after brain injury. In addition, angiogenesis and neurogenesis are coupled through VEGF, angiopoietins (Ang)1 and SDF1α. Brain remodeling, including angiogenesis and neurogenesis, may contribute to spontaneous and therapy-promoted functional recovery after brain injury. The symbol (+) in the figure indicates positive effects.