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(Circulation Research. 2004;95:364.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Minocycline Exerts Multiple Inhibitory Effects on Vascular Endothelial Growth Factor–Induced Smooth Muscle Cell Migration

The Role of ERK1/2, PI3K, and Matrix Metalloproteinases

Jianhua S. Yao, Yongmei Chen, Wenwu Zhai, Kaiyan Xu, William L. Young, Guo-Yuan Yang

From the The Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative Care (J.S.Y., Y.C., W.L.Y., G.-Y.Y.), Neurological Surgery (W.L.Y., G.-Y.Y.), and Neurology (W.L.Y.), Lung Biology (W.Z.), and Gladstone Institute (K.X.), University of California, San Francisco.

Correspondence to Guo-Yuan Yang, MD, PhD, The Center for Cerebrovascular Research, Departments of Anesthesia and Neurosurgery, UCSF, 1001 Potrero Ave, Box 1371, San Francisco, CA 94110. E-mail gyyang{at}anesthesia.ucsf.edu

Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation, migration, and matrix remodeling. We examined whether minocycline inhibited human aortic smooth muscle cell (HASMC) migration induced by vascular endothelial growth factor (VEGF).

After the establishment of an optimal dose, minocycline treated HASMC were exposed to VEGF. HASMC migration, matrix metalloproteinase (MMP)-2 and MMP-9 activities, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) phosphorylation were determined by smooth muscle cell (SMC) invasion assay, real-time polymerase chain reaction, zymograms, and Western blot analysis, respectively.

We demonstrated that VEGF and platelet-derived growth factor (PDGF)-induced SMC migration in a dose-dependent manner. MMP-9, but not MMP-2, mRNA was increased during VEGF stimulation. MMP-9 activity was increased from 1.5- to 2.5-fold in a dose-dependent manner (P<0.05). Both ERK1/2 and PI3K/AKt pathways were activated during VEGF-induced HASMCs migration. We then demonstrated that minocycline can inhibit VEGF-induced HASMC migration (P<0.05). The effects may be through the inhibition of MMP-9 mRNA transcription, protein activities and downregulation of ERK1/2 and PI3K/Akt pathway phosphorylation.

Our results indicated that minocycline exerts multiple effects on VEGF-induced SMC migration, including inhibition of MMP-9 mRNA transcription and protein activities and downregulating ERK1/2 and PI3K signal pathways, suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis.

Key Words: matrix metalloproteinase • minocycline • migration • smooth muscle cell • vascular endothelial growth factor

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