p38 MAP kinase mediates transforming-growth factor-β1-induced upregulation of matrix metalloproteinase-9 but not -2 in human brain pericytes

Yoko Takahashi, Takakuni Maki, Anna C. Liang, Kanako Itoh, Josephine Lok, Noriko Osumi, Ken Arai

研究成果: ジャーナルへの寄稿学術論文査読

23 被引用数 (Scopus)

抄録

Pericytes are vascular mural cells embedded within the basal lamina of blood micro-vessels. Within the neurovascular unit, pericytes play important roles in regulating neurovascular homeostasis by secreting soluble factors, such as matrix metalloproteinases (MMPs). However, little is known about the regulatory signaling pathways in brain pericytes. Here we show that transforming growth factor-β1 (TGF-β1) induces MMP-9 upregulation in pericytes via p38 mitogen-activated protein (MAP) kinase signaling. Cultured human brain vascular pericytes were used in this study. When the brain pericytes were treated with purified human TGF-β1 (0.1-10 ng/mL for 24 h), the levels of MMP-2 and MMP-9 in culture media were significantly increased in a concentration dependent manner as measured by gelatin zymography. WST assay confirmed that TGF-β1 did not affect cell survival of the brain pericytes. A TGF-β-receptor inhibitor SB431542 (0.5-5 μM) decreased the TGF-β1-induced upregulation of MMP-2 and MMP-9. To assess the underlying intracellular mechanisms, we focused on p38 MAP kinase signaling, which is one of the major downstream kinases for TGF-β1. A well-validated p38 MAP kinase inhibitor SB203580 (0.5-5 μM) cancelled the effect of TGF-β1 in upregulation of MMP-9 but not MMP-2. Western blotting confirmed that TGF-β1 treatment increased the level of p38 MAP kinase phosphorylation in pericytes, and again, the TGF-β-receptor inhibitor SB431542 (0.5-5 μM) blocked the TGF-β1-induced phosphorylation of p38 MAP kinase. Both TGF-β1 and MMP-9 are major neurovascular mediators, and therefore, our current finding may suggest a novel mechanism for how pericytes regulate neurovascular homeostasis.

本文言語英語
ページ(範囲)1-8
ページ数8
ジャーナルBrain Research
1593
DOI
出版ステータス出版済み - 2014 12月 17

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