Abstract 11947: Rapid, Non-nuclear Estrogen Receptor Signaling is Critical for Estrogen-mediated Inhibition of Vascular Smooth Muscle Cell Proliferation
Background: The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases such as atherosclerosis and restenosis after PCI. Although abundant evidence from animal studies has shown that estrogen is potentially protective against vascular injury, the mechanisms that mediate estrogen’s protective effects remain unclear. Recent studies have shown that estrogen signals through a rapid, non-nuclear signaling pathway, in addition to a canonical genomic pathway, that does not directly involve regulation of gene expression. We previously reported that the rapid signaling pathway is selectively blocked by overexpression of a peptide comprised of amino acids 176-253 of estrogen receptor (ER) α that prevents ER from joining the signaling complex required for rapid signaling. Here we established transgenic mice, disrupting peptide mice (DPM), which overexpress this disrupting peptide, and investigated the role of rapid signaling in estrogen’s effects on VSMC proliferation.
Methods and Results: Carotid artery VSMCs from DPM or littermate WT female mice were obtained by the explant method. In VSMC derived from WT, estrogen significantly inhibited serum- or platelet-derived growth factor (PDGF)-stimulated VSMC proliferation (17.4±1.49% or 14.0±1.89% inhibition, respectively, p<0.01). Phosphorylation levels of protein kinases such as ERKs and Akt induced by PDGF were significantly inhibited by estrogen pre-treatment. Estrogen had no effect on VSMC proliferation, or PDGF-stimulated kinase activation in VSMC derived from DPM. Estrogen enhanced the binding between ERα and a phosphatase, PP2A, and enhanced PP2A activity in VSMC from WT, but not in VSMC from DPM. Pharmacologic blockade of PP2A abolished the estrogen-induced inhibition of phosphorylation of the kinases and the anti-proliferative effect on VSMC.
Conclusions: These results support that rapid ER signaling is required for estrogen-induced inhibition of VSMC proliferation, and that PP2A activation by estrogen mediates estrogen-induced anti-proliferative effects. These findings support that rapid ER signaling may be a novel target for therapeutic approaches to inhibit VSMC proliferation, which plays a central role in atherosclerosis and restenosis.
- © 2012 by American Heart Association, Inc.