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Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5

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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.

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Acknowledgments

This work was supported by a Postdoctoral Fellowship Award from the American Heart Association (AB) and by the NIH RO1 Grant NS060770 (RM). This is manuscript number 27010 from The Scripps Research Institute.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All experiments performed in this study comply with the current laws of the United States of America.

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Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, MEM-132, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Amin Boroujerdi, Jennifer V. Welser-Alves & Richard Milner

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  1. Amin Boroujerdi
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  2. Jennifer V. Welser-Alves
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  3. Richard Milner
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Correspondence to Richard Milner.

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Boroujerdi, A., Welser-Alves, J.V. & Milner, R. Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5. Angiogenesis 18, 255–264 (2015). https://doi.org/10.1007/s10456-015-9464-7

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  • DOI: https://doi.org/10.1007/s10456-015-9464-7

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