The extent of vascular remodeling is dependent on the balance between ERα and GPER(GPR30)
Bibliographic record
Abstract
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).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".