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

Article type: Research Article

Authors: Huang, Qijuan^{b; e; 1} | Chen, Bing^{c; 1} | Wang, Fuxin^b | Huang, Heng^b | Milner, Richard^{d; *} | Li, Longxuan^{a; b; *}

Affiliations: [a] Department of Neurology, Gongli Hospital, Pudong New District, Shanghai, P. R. China | [b] Department of Neurology, Guangdong Medical College Affiliated Hospital, Zhanjiang, P. R. China | [c] Department of Neurosurgery, Guangdong Medical College Affiliated Hospital, Zhanjiang, P. R. China | [d] Department of Molecular and Experimental Medicine, The Scripps Research Institute, North Torrey Pines Road, La Jolla, CA, USA | [e] Department of Neurology, Taishan People’s Hospital, Taishan, P. R. China

Correspondence: [*] Corresponding author: Richard Milner, Department of Mole-cular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Tel.:+1 858 784 8569; Fax: +1 858 784 2174; [email protected]

Correspondence: [*] Corresponding author: Longxuan Li, Dept. of Neurology, Gongli Hospital,219 Miaopu Road, Pudong New Area, Shanghai 200135, P. R. China. Tel.: +86 21 5885 8730; Fax: +86 21 5885 8640; [email protected].

Note: [1] Qijuan Huang and Bing Chen contributed equally to this work.

Abstract: Purpose: We previously demonstrated that 7 days post-ischemia, angiogenic vessels in the ischemic penumbra show strong upregulation of fibronectin (Fn) and its receptors, α5β1 and αvβ3 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 α5 and β3 integrins peaked at day 7, and this coincided exactly with maximal endothelial proliferation. Conclusions: Our results suggest that upregulation of the Fn-α5β1/αVβ3 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.

Keywords: Cerebral ischemia, angiogenesis, endothelial proliferation, integrin, fibronectin, glia

DOI: 10.3233/RNN-140491

Journal: Restorative Neurology and Neuroscience, vol. 33, no. 4, pp. 493-507, 2015