Nontranscriptional activation of PI3K/Akt signaling mediates hypotensive effect following activation of estrogen receptor β in the rostral ventrolateral medulla of rats.
BACKGROUND
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. 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.


METHODS
In 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.


RESULTS
Similar 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 × 10(8) pfu) reversed the vasodepressive effects of DPN.


CONCLUSIONS
Our 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.
Department of Pharmacy, Graduate Institute of Pharmaceutical Technology, Tajen University, 20 Weishin Road, Yanpu Township, Pingtung County 90741, Taiwan.
Kay L H
KL
Wu
Chen-Hsiu
CH
Chen
Cheng-Dean
CD
Shih
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D007022:Hypotension / Q000378:metabolism*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047629:Estrogen Receptor beta; D009570:Nitriles; D011422:Propionates; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt