Mechanisms and targets for angiogenic therapy after stroke

Abstract

Stroke remains a major health problem worldwide, and is the leading cause of serious long-term disability. Recent findings now suggest that strategies to enhance angiogenesis after focal cerebral ischemia may provide unique opportunities to improve clinical outcomes during stroke recovery. In this mini-review, we survey emerging mechanisms and potential targets for angiogenic therapies in brain after stroke. Multiple elements may be involved, including growth factors, adhesion molecules and progenitor cells. Furthermore, cross talk between angiogenesis and neurogenesis may also provide additional substrates for plasticity and remodeling in the recovering brain. A better understanding of the molecular interplay between all these complex pathways may lead to novel therapeutic avenues for tackling this difficult disease.

Figure 1

Endogenous angiogenesis occurs in the post-ischemic penumbra. Scanning electron microscopy images of leptomeningeal (large arrows) and small penetrating arterioles (small arrows) in normal brain (A and B). (C) Areas of infarction where no blood vessels are visible (arrow), and (D) stressed microvessels 24 h after MCAO. (E and F) Vascular buds were visible three days after MCAO (arrows), and (G and H) connections or ‘nests’ of small microvessels associating with surrounding vessels (arrows). Size is shown in the inserted bars. Adapted from Slevin et al. Clinical Science 2006; 171–83.

Figure 2

Exogenous VEGF can be directly neurotoxic. Histological analysis of untreated normal brain (A), normal brain treated by the low dose of VEGF165 (B), normal brain treated by the intermediate dose of VEGF165 (C), and normal brain treated by the high dose of VEGF165 (D). The histology of untreated normal brain, normal brain treated by the low dose of VEGF165, and normal brain treated by the intermediate dose of VEGF165 (C) is similar. In contrast, the adverse effects of the high dose of VEGF165 on histology of the neurons and neuropil are conspicuous. Bar = 25 µm. Adapted from Manoonkitiwongsa et al. Vascular Pharmacology 2006; 44:316–25.

Figure 3

A peptide antagonist to VE-cadherin inhibits retinal angiogenesis without disrupting endothelial cell junctions. (A) VE-cadherin antagonist blocks retinal angiogenesis in a mouse model of oxygen-induced retinopathy in a dose-dependent manner. (B) The vascular endothelial cadherin (VE-cadherin) antagonist does not disrupt existing endothelial cell junctions. Representative images of confluent bovine retinal endothelial cell monolayers stained for VE-cadherin in untreated (I), control peptide-treated (II), and antagonist-treated (III) cells. The antagonist had no effect on the structural integrity of the monolayer as demonstrated by continuous VE-cadherin staining along the cell borders. Bars indicate 10 µm. (D) The function of the cell junctions was assessed by measuring the permeability of the monolayer using fluorescein isothiocyanate-dextran. The permeability of the antagonist-treated cells was not significantly different from untreated cells or cells treated with control peptide. Adapted from Navaratna et al. Archives of Ophthalmology 2008; 126:1082–8.

Figure 4

Neurorestorative processes and strategies in post-acute stroke therapy. Angiogenesis is critical to neurogenesis and neuroprotection and a combinatorial platform with growth factors, adhesion molecule modifiers and cellular therapies might provide an optimal solution for promoting angiogenesis in the brain.