Abstract
BackgroundEstrogen acts on the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, to elicit vasodepressor effects via an estrogen receptor (ER)β-dependent mechanism. We investigated in the present study nontranscriptional mechanism on cardiovascular effects following activation of ERβ in the RVLM, and delineated the involvement of phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway in the effects.MethodsIn male Sprague–Dawley rats maintained under propofol anesthesia, changes in arterial pressure, heart rate and sympathetic neurogenic vasomotor tone were examined after microinjection bilaterally into RVLM of 17β-estradiol (E2β) or a selective ERα or ERβ agonist. Involvement of ER subtypes and PI3K/Akt signaling pathway in the induced cardiovascular effects were studied using pharmacological tools of antagonists or inhibitors, gene manipulation with antisense oligonucleotide (ASON) or adenovirus-mediated gene transfection.ResultsSimilar to E2β (1 pmol), microinjection of ERβ agonist, diarylpropionitrile (DPN, 1, 2 or 5 pmol), into bilateral RVLM evoked dose-dependent hypotension and reduction in sympathetic neurogenic vasomotor tone. These vasodepressive effects of DPN (2 pmol) were inhibited by ERβ antagonist, R,R-tetrahydrochrysene (50 pmol), ASON against ERβ mRNA (250 pmol), PI3K inhibitor LY294002 (5 pmol), or Akt inhibitor (250 pmol), but not by ERα inhibitor, methyl-piperidino-pyrazole (1 nmol), or transcription inhibitor, actinomycin D (5 or 10 nmol). Gene transfer by microinjection into bilateral RVLM of adenovirus encoding phosphatase and tensin homologues deleted on chromosome 10 (5 × 108 pfu) reversed the vasodepressive effects of DPN.ConclusionsOur results indicate that vasodepressive effects following activation of ERβ in RVLM are mediated by nongenomic activation of PI3K/Akt signaling pathway. This study provides new insight in the intracellular signaling cascades involved in central vasodepressive functions of estrogen.
Highlights
Estrogen acts on the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, to elicit vasodepressor effects via an estrogen receptor (ER)β-dependent mechanism
Cardiovascular effects following microinjection bilaterally into the RVLM of E2β, ERα or ERβ agonist Compared with artificial cerebrospinal fluid (aCSF) treatment, bilateral microinjection of E2β (1 pmol) into the functionally identified pressor region of RVLM resulted in significant decreases in mean systemic arterial pressure (SAP) (MSAP) and power density of vasomotor components of SAP spectrum, our experimental index for sympathetic neurogenic vasomotor outflow [17,22,23,27,30,32], with no apparent change in heart rate (HR) (Figure 1)
Effects of ER antagonist on the ERβ agonist-induced vasodepressive responses Compared with aCSF or 5 % dimethyl sulfoxide (DMSO) controls, coadministration bilaterally into the RVLM of a nonspecific ER antagonist, ICI 182780 (0.25 or 0.5 pmol) significantly attenuated the vasodepressive responses of DPN (2 pmol) in a dose-dependent manner (Figure 2)
Summary
Estrogen acts on the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, to elicit vasodepressor effects via an estrogen receptor (ER)β-dependent mechanism. In the heart and peripheral blood vessels, nongenomic mechanisms underlie estrogen-induced rapid arterial vasodilation [5,6], inhibition of atherosclerotic lesions [5,8], cardioprotective effect following trauma-hemorrhage [7], and amelioration of ischemia/ reperfusion-induced myocardial injury [9] These nongenomic actions of estrogen are thought to be mediated via activation of the phosphatidylinositol 3-kinase (PI3K) [57] and serine/threonine kinase Akt (Akt) [5,7] signaling cascades following direct activation by the hormone of the cellular membrane rather than intracellular receptors [4,5,7,10]
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