Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

Abstract

Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes specific growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endothelial progenitor cells migrate and home to specific sites following ischemic stroke via growth factor/cytokine gradients. Some growth factors are less stable under acidic conditions of tissue ischemia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovascularization following ischemic stroke.

Keywords: cytokine; endothelial progenitor cells; growth factor; ischemic stroke; mobilization; neovascularization.

Figure 1

Homing and functional role of endothelial progenitor cells (EPCs) in post-cerebral ischemia. EPCs migrate from the bone marrow via blood vessels to sites of tissue injury and ischemia. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 are critical mediators for ischemia-specific recruitment of circulating EPCs. Hypoxia-induced vascular endothelial growth factor (VEGF) expression precedes neovascularization after cerebral ischemia. Early EPCs secrete mainly proangiogenic cytokines including VEGF, placental growth factor, transforming growth factor-β, thrombopoietin, hepatocyte growth factor, fibroblast growth factor, macrophage migration inhibitory factor, macrophage colony stimulating factor, interleukin-8, as well as a few antiangiogenic cytokines, and also neurotrophic and neuroregulatory cytokines including brain-derived neurotrophic factor.