Angiogenesis and neuronal remodeling after ischemic stroke

Abstract

Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models.This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets.

Keywords: angiogenesis; axonal outgrowth; cerebral ischemia; coupling; functional recovery; guidance; neurogenesis; stroke.

Figure 1

The schema of association between angiogenesis and axonal outgrowth. After ischemia, several mediators, such as vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), brain-derived neurotrophic factor (BDNF), platelet-derived growth factor-B (PDGF-B), angiopoietin-1 (Ang-1), and progranulin, may promote both angiogenesis and axonal outgrowth, coupled with cells comprising the neurovascular units.

Figure 2

The angiogenesis guides axonal outgrowth and neurogenesis. Vascular endothelial growth factor (VEGF) and several factors from hypoxic tissues and microvessels promote angiogenesis several days after cerebral ischemia. After intervention, (1) new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by VEGF and laminin/β1-integrin signaling. (2) Vascular-guided neural stem/progenitor cells (NSCs) also may migrate peri-infarct regions and migrated NSCs differentiate into mature neurons several weeks after cerebral ischemia. SGZ: Subgranular zone; SVZ: subventricular zone.