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Rapid estrogen receptor-α signaling mediated by ERK activation regulates vascular tone in male and ovary-intact female mice.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2018 Feb 01; Vol. 314 (2), pp. H330-H342. Date of Electronic Publication: 2017 Sep 08. - Publication Year :
- 2018
-
Abstract
- Estrogen has been shown to affect vascular reactivity. Here, we assessed the estrogen receptor-α (ERα) dependency of estrogenic effects on vasorelaxation via a rapid nongenomic pathway in both male and ovary-intact female mice. We compared the effect of a primary estrogen, 17β-estradiol (E <subscript>2</subscript> ) or 4,4',4″-(4-propyl-[1H]pyrazole-1,3,5-triyl)tris-phenol (PPT; selective ERα agonist). We found that E <subscript>2</subscript> and PPT induced greater aortic relaxation in female mice than in male mice, indicating ERα mediation, which was further validated by using ERα antagonism. Treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP dihydrochloride; ERα antagonist) attenuated PPT-mediated vessel relaxation in both sexes. ERα-mediated vessel relaxation was further validated by the absence of significant PPT-mediated relaxation in aortas isolated from ERα knockout mice. Treatment with a specific ERK inhibitor, PD-98059, reduced E <subscript>2</subscript> -induced vessel relaxation in both sexes but to a lesser extent in female mice. Furthermore, PD-98059 prevented PPT-induced vessel relaxation in both sexes. Both E <subscript>2</subscript> and PPT treatment activated ERK as early as 5-10 min, which was attenuated by PD-98059 in aortic tissue, cultured primary vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). Aortic rings denuded of endothelium showed no differences in vessel relaxation after E <subscript>2</subscript> or PPT treatment, implicating a role of ECs in the observed sex differences. Here, our results are unique to show estrogen-stimulated rapid ERα signaling mediated by ERK activation in aortic tissue, as well as VSMCs and ECs in vitro, in regulating vascular function by using side-by-side comparisons in male and ovary-intact female mice in response to E <subscript>2</subscript> or PPT. NEW & NOTEWORTHY Here, we assessed the estrogen receptor-α dependency of estrogenic effects in vasorelaxation of both male and ovary-intact female mice by performing side-by-side comparisons. Also, we describe the connection between estrogen-stimulated rapid estrogen receptor-α signaling and downstream ERK activation in regulating vascular function in male and ovary-intact female mice.
- Subjects :
- Animals
Aorta, Thoracic enzymology
Cells, Cultured
Dose-Response Relationship, Drug
Endothelial Cells drug effects
Endothelial Cells enzymology
Enzyme Activation
Estrogen Receptor alpha deficiency
Estrogen Receptor alpha genetics
Female
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular enzymology
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle enzymology
Sex Factors
Signal Transduction drug effects
Aorta, Thoracic drug effects
Estradiol pharmacology
Estrogen Receptor alpha drug effects
Extracellular Signal-Regulated MAP Kinases metabolism
Phenols pharmacology
Pyrazoles pharmacology
Vasodilation drug effects
Vasodilator Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 314
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 28887333
- Full Text :
- https://doi.org/10.1152/ajpheart.00841.2016