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MMP-2 Is Mainly Expressed in Arterioles and Contributes to Cerebral Vascular Remodeling Associated with TGF-β1 Signaling

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Abstract

There is increasing evidence to suggest that matrix metalloproteinases (MMPs) play a crucial role in vascular remodeling. It has been reported that hypoxia stimulated MMP-9 expression in brain endothelial cells and MMP-9 plays an important role in cerebral vascular remodeling. However, little is known about MMP-2 in the cerebral vessels remodeling. Herein, the aim of this study is to examine the class of vessel and cell type expressing MMP-2 in cerebral vessels and to investigate its potential role in vascular remodeling. In the present study, dual-immunofluorescence assay showed that MMP-2 was mainly expressed in arterioles. In addition, we found that MMP-2 expression in cerebral vessels was derived from endothelial cells, not astrocyte cells. Notably, in the normoxic central nervous system (CNS), there was no effect on vascular development, integrity, or endothelial proliferation when MMP-2 was knocked out, but lack of MMP-2 led to defective arteriolar remodeling and associated with transforming growth factor β1 (TGF-β1) signaling in CNS. Moreover, blocking TGF-β with SB431542, a specific TGF-β inhibitor, significantly reduced the messenger RNA (mRNA) and protein expression levels of MMP-2 in human umbilical vein endothelial cells (HUVECs). Our findings reveal that the level of MMP-2 is high in arteriolar endothelial cells and demonstrate a novel connection between MMP-2 and TGF-β1 signaling in cerebral vascular remodeling.

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Correspondence to Yunnan Lu.

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Funding

This work was supported by Medical Development Funding (7632932).

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Supplementary Fig. 1

H&E staining and immunohistochemistry of mice brain sections. A, The brain regions of cerebral cortex and hippocampus were examined by H&E staining. B, The association of MMP-2 expression and cell-specific markers in cerebral vessels. The sections of hippocampus from mice were performed immunohistochemistry analysis by confocal microscopy. The antibodies specific for MMP-2 (AlexaFluor-488, green), endothelial marker CD31 (Cy3, red), astrocyte marker GFAP (Cy3, red), smooth muscle cell marker α-SMA (Cy3, red), or neuronal cell marker Map2 (Cy3, red) were used. Scale bars, 100 μm (GIF 97 kb)

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Hua, Y., Zhang, W., Xie, Z. et al. MMP-2 Is Mainly Expressed in Arterioles and Contributes to Cerebral Vascular Remodeling Associated with TGF-β1 Signaling. J Mol Neurosci 59, 317–325 (2016). https://doi.org/10.1007/s12031-015-0687-2

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  • DOI: https://doi.org/10.1007/s12031-015-0687-2

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