Premium
The extent of vascular remodeling is dependent on the balance between ERα and GPER(GPR30)
Author(s) -
Gros Robert,
Ding Qingming,
Hussain Yasin,
Chorazyczewski Jozef,
Pickering Geoffery,
Feldman Ross D
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1189.1
Subject(s) - gper , medicine , endocrinology , estrogen receptor , estrogen , vascular smooth muscle , receptor , chemistry , biology , microbiology and biotechnology , cancer , smooth muscle , breast cancer
Estrogens are important physiological and pathophysiological regulators of cardiovascular function. The traditional view of the mechanism for these cardiovascular effects has focused on the activation of “classical” steroid receptors (i.e., estrogen receptors‐ERs). However, recent studies have elucidated the mechanism of estrogen's cardiovascular effects mediated by an alternate GPCR‐based mechanism viz., via GPER (aka GPR30), formerly characterized as an “orphan receptor”. We are beginning to appreciate that to understand the effect of estradiol in cardiovascular regulation one must understand the balance between GPER‐ and ER‐mediated effects. In vascular smooth muscle cells, estrogen‐mediated regulation of apoptotic cell death and proliferation is divergently regulated by activation of ER vs. GPER. However, the significance of this divergence in the in vivo regulation of vascular growth processes was unknown. To determine the role of GPER in regulating vascular remodeling we studied the effects of altering GPER expression vs. altering the expression of ERα in a rat model of carotid ligation. Under baseline conditions, 1 week following carotid ligation and endothelial disruption with distilled water installation there was a 51±7.6% (n=3) increase in medial thickness, paralleling neointimal proliferation in female rats. This medial hypertrophy paralleled down‐regulation of GPER protein content (26±5% of control; n=3) and mRNA expression (29±13% of control; n=3). Re‐introduction of GPER, via abluminal adenoviral delivery, significantly attenuated the extent of medial hypertrophy (adeno‐GPER: 28±2.2% increase; n=10 vs. adeno‐GFP/control: 48±3.3% increase; n=16, p<0.05). Similarly, inhibition of ERα expression using an adeno‐shERαRNA construct resulted in an attenuation of injury‐mediated medial hypertrophy. In these studies we show that in vivo the balance between GPER and ERα is a significant regulator in the extent of vascular remodeling. Receptor‐specific modulation of estrogen's growth regulatory effects may be an important new approach in modifying the extent of vascular remodeling in both acute settings like vascular injury and perhaps in longer term models of regulation like in hypertension. Support or Funding Information These studies were supported by grants from the Heart and Stroke Foundation of Canada (RG and RDF).