Abstract 13546: Rapid, Non-Nuclear Estrogen Receptor Signaling is Required for Estrogen-mediated Inhibition of Vascular Smooth Muscle Cell Proliferation in vitro and in vivo
Background: The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases such as atherosclerosis. We and others have previously shown that estrogen protects against vascular injury in the mouse carotid injury model. The mechanisms that mediate these effects remain unclear. Estrogen signals via a canonical genomic pathway in which ligand-bound estrogen receptor (ER) transcriptionally regulates gene expression. Recent studies have shown that estrogen also signals through a rapid, kinase-mediated, non-nuclear signaling pathway that does not directly involve regulation of gene expression. We previously reported that activation of the rapid, non-nuclear pathway by estrogen requires binding between the ER and striatin, a caveolin-binding protein, and that this complex formation, and the rapid signaling, is selectively blocked (i.e. without altering genomic signaling) by over-expression of a peptide comprised of amino acids 176-253 of ERalpha. In this study, we established transgenic mice, ER176-253 TG mice, which overexpress the peptide that disrupts complex formation between ERalpha and striatin, and investigated the role of the estrogen's rapid, non-nuclear ER signaling pathway in estrogen's inhibitory effects on VSMC proliferation.
Methods and Results: Aortic VSMCs from ER176-253 TG or littermate WT female mice were obtained by the explant method. In vitro, estrogen (100nM) significantly inhibited serum-stimulated VSMC proliferation of cells derived from WT mice (p<0.01, n=4 per condition), but had no effect on ER176-253-derived VSMC. Next, ovariectomized, female mice were subjected to wire injury to carotid artery. Estrogen significantly inhibited the increase of VSMC proliferation (assessed by BrdU uptake) (134.5±28.1 vs 54.5±4.1 BrdU positive VSMC/section, p<0.001, n=10) and thickening of medial area (25.0±1.7 vs 19.9±1.4 x10-3 mm2, p=0.02, n=10) after injury in WT mice, but these effects were abolished in ER176-253 TG mice.
Conclusions: These results support that the rapid, non-nuclear ER-mediated signaling is required for estrogen-induced inhibition of VSMC proliferation in vitro and in vivo and suggest that new drugs acting in pathway specific manner provide selective vascular benefit.
- © 2011 by American Heart Association, Inc.