title: Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5.
abstract: Vascular remodeling involves a highly coordinated break-down and build-up of the vascular basal lamina and inter-endothelial tight junction proteins. In light of the important role of matrix metalloproteinases (MMPs) in tissue remodeling, the goal of this study was to examine the role of MMP-9 in remodeling of cerebral blood vessels, both in hypoxia-induced angiogenesis and in the vascular pruning that accompanies the switch from hypoxia back to normoxia. In a chronic mild hypoxia model of cerebrovascular remodeling, gel zymography revealed that MMP-9 levels were increased, both during hypoxic-induced angiogenesis and in the post-hypoxic pruning response. Interestingly, compared to wild-type mice, MMP-9 KO mice showed no alteration in hypoxic-induced angiogenesis, but did show marked delay in post-hypoxic vascular pruning. In wild-type mice, vascular pruning was associated with fragmentation of vascular laminin and the tight junction protein claudin-5, while this process was markedly attenuated in MMP-9 KO mice. In vitro experiments showed that hypoxia stimulated MMP-9 expression in brain endothelial cells but not pericytes. These results show that while MMP-9 is not essential for hypoxic-induced cerebral angiogenesis, it plays an important role in post-hypoxic vascular pruning by degrading laminin and claudin-5.
authors: Department of Molecular and Experimental Medicine, MEM-132, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Amin
authors: A
authors: Boroujerdi
authors: Jennifer V
authors: JV
authors: Welser-Alves
authors: Richard
authors: R
authors: Milner
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D062507:Claudin-5 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D000860:Hypoxia; D007150:Immunohistochemistry; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020286:Pericytes / Q000166:cytology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D066253:Vascular Remodeling
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse