The temporal expression patterns of fibronectin and its receptors-α5β1 and αvβ3 integrins on blood vessels after cerebral ischemia

Purpose: We previously demonstrated that 7 days post-ischemia, angiogenic vessels in the ischemic penumbra show strong upregulation of fibronectin (Fn) and its receptors, alpha 5 beta 1 and alpha v beta 3 integrins. The aim of the current study was to precisely define the time-course of angiogenic responses and glial activation following experimental ischemia in the mouse. Methods: Male C57Bl/6 mice were subject to 90 minutes of ischemia by temporary occlusion of the middle cerebral artery followed by reperfusion. Vascular remodeling and glial activation were then examined in the brains of these mice after 0, 1, 2, 4, 7 and 14 days post-ischemia. Results: Immunofluorescent studies demonstrated that in the ischemic penumbra, blood vessel density increased up to day 14. In contrast, within the ischemic core, vessel density declined, reaching a low point at day 4, but then started to increase. In the penumbra, expression of Fn and the alpha 5 and beta 3 integrins peaked at day 7, and this coincided exactly with maximal endothelial proliferation. Conclusions: Our results suggest that upregulation of the Fn-alpha 5 beta 1 and alpha v beta 3 integrin axis on blood vessels stimulates BEC proliferation at an early stage of angiogenesis post-ischemia. This could form the basis of novel therapeutic strategies aimed at promoting angiogenesis following cerebral ischemia.