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Exp Cell Res. 2013 Nov 15;319(19):3042-50. doi: 10.1016/j.yexcr.2013.08.014. Epub 2013 Aug 19.

Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor.

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  • 1Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521, Japan; Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522, Japan. Electronic address:


Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned medium significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation.

© 2013 Published by Elsevier Inc.


1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine; 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt; 4-(3-phenoxyphenyl)-5-cyano-2H-1,2,3-triazole; AGE; AR; CDK4; CPAP; ER; Epidermal growth factor; ErbB2 inhibitor II; HIF-1; IH; Intermittent hypoxia; NRG1; OSA; POD; PVDF; RASMC; ROS; SH; TBS-T; TEMPOL; VSMC; Vascular smooth muscle cell; WST-8; advanced glycation end product; amphiregulin; continuous positive airway pressure; cyclin-dependent kinase 4; epiregulin; erbB2 receptor; hypoxia inducible factor-1; intermittent hypoxia; neuregulin-1; obstructive sleep apnea; peroxidase; polyvinylidene difluoride; rat aortic smooth muscle cell; reactive oxygen species; sustained hypoxia; tris-buffered saline containing 0.1% Tween-20; vascular smooth muscle cell

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