• the Korean Society for Brain and Neural Sciences


Original Article

Exp Neurobiol 2018; 27(4): 299-308

Published online August 30, 2018

© The Korean Society for Brain and Neural Sciences

Chronic Cerebral Hypoperfusion Induces Alterations of Matrix Metalloproteinase-9 and Angiopoietin-2 Levels in the Rat Hippocampus

Min-Soo Kim1,4,5,†, Bo-Ryoung Choi1,†, Yong Woo Lee2, Dong-Hee Kim1, Ye Sun Han3, Won Kyung Jeon4,5*, and Jung-Soo Han1*

1Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.

2Department of Biomedical Sciences and Pathobiology, School of Biomedical Engineering and Sciences, Virginia Tech, Virginia 24061, USA.

3Department of Advanced Technology Fusion, Konkuk University, Seoul 05029, Korea.

4Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.

5Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea.

Correspondence to: *To whom correspondence should be addressed.
Jung-Soo Han, TEL: 82-2-450-3293, FAX: 82-2-3436-5432
Won Kyung Jeon,TEL: 82-42-868-9505, FAX: 82-42-861-5800
These authors contributed equally

Received: March 12, 2018; Revised: August 3, 2018; Accepted: August 3, 2018

Angiogenic factors contribute to cerebral angiogenesis following cerebral hypoperfusion, and understanding these temporal changes is essential to developing effective treatments. The present study examined temporal alterations in angiogenesis-related matrix metalloproteinase-9 (MMP-9) and angiopoietin-2 (ANG-2) expression in the hippocampus following bilateral common carotid artery occlusion (BCCAo). Male Wistar rats (12 weeks of age) were randomly assigned to sham-operated control or experimental groups, and expression levels of MMP-9 and ANG-2 were assessed after BCCAo (1 week, 4 weeks, and 8 weeks), using western blotting. Protein expression increased 1 week after BCCAo and returned to control levels at 4 and 8 weeks. In addition, immunofluorescence staining demonstrated that the MMP-9- and ANG-2-positive signals were primarily observed in the NeuN-positive neurons with very little labeling in non-neuronal cells and no labeling in endothelial cells. In addition, these cellular locations of MMP-9- and ANG-2-positive signals were not altered over time following BCCAo. Other angiogenic factors such as vascular endothelial growth factor and hypoxia-inducible factor did not differ from controls at 1 week; however, expression of both factors increased at 4 and 8 weeks in the BCCAo group compared to the control group. Our findings increase understanding of alterations in angiogenic factors during the progression of cerebral angiogenesis and are relevant to developing effective temporally based therapeutic strategies for chronic cerebral hypoperfusion-associated neurological disorders such as vascular dementia.

Graphical Abstract

Keywords: BCCAo, Angiogenesis, Angiopoietin-2, Matrix metalloproteinase-9, Vascular dementia