Nontranscriptional Activation of PI3K/Akt Signaling Mediates Hypotensive Effect Following Activation of Estrogen Receptor β in the Rostral Ventrolateral Medulla of Rats

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2012 Aug 18

PMID 22897791

Citations 10

Authors

Kay L H Wu

Chen-Hsiu Chen

Cheng-Dean Shih

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.

Wang X, Feng S, Deng Q, Wu C, Duan R, Yang L Mol Cell Biochem. 2024; .

PMID: 39088186 DOI: 10.1007/s11010-024-05071-4.

Estrogen dampens central cannabinoid receptor 1-mediated neuroexcitation and pressor response in conscious female rats.

Yao F, Abdel-Rahman A Biochem Pharmacol. 2022; 201:115102.

PMID: 35617998 PMC: 9399937. DOI: 10.1016/j.bcp.2022.115102.

Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway.

Li S, Lei Z, Yang X, Zhao M, Hou Y, Wang D Front Pharmacol. 2022; 13:841410.

PMID: 35370724 PMC: 8966655. DOI: 10.3389/fphar.2022.841410.

Gengnianchun Recipe Protects Ovarian Reserve of Rats Treated by 4-Vinylcyclohexene Diepoxide via the AKT Pathway.

Zhao F, Wang W Int J Endocrinol. 2020; 2020:9725898.

PMID: 33381174 PMC: 7758144. DOI: 10.1155/2020/9725898.

Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats.

Steagall R, Yao F, Shaikh S, Abdel-Rahman A Life Sci. 2017; 182():41-49.

PMID: 28599865 PMC: 5535783. DOI: 10.1016/j.lfs.2017.06.005.

References

Nathan L, Pervin S, Singh R, Rosenfeld M, Chaudhuri G . Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis. Circ Res. 1999; 85(4):377-85. DOI: 10.1161/01.res.85.4.377. View

Wang G, Drake C, Rozenblit M, Zhou P, Alves S, Herrick S . Evidence that estrogen directly and indirectly modulates C1 adrenergic bulbospinal neurons in the rostral ventrolateral medulla. Brain Res. 2006; 1094(1):163-78. DOI: 10.1016/j.brainres.2006.03.089. View

Chang A, Chan J, Chou J, Li F, Dai K, Chan S . Heat shock protein 60 in rostral ventrolateral medulla reduces cardiovascular fatality during endotoxaemia in the rat. J Physiol. 2006; 574(Pt 2):547-64. PMC: 1817760. DOI: 10.1113/jphysiol.2006.110890. View

Shih C, Chuang Y . Nitric oxide and GABA mediate bi-directional cardiovascular effects of orexin in the nucleus tractus solitarii of rats. Neuroscience. 2007; 149(3):625-35. DOI: 10.1016/j.neuroscience.2007.07.016. View

Spary E, Maqbool A, Batten T . Oestrogen receptors in the central nervous system and evidence for their role in the control of cardiovascular function. J Chem Neuroanat. 2009; 38(3):185-96. DOI: 10.1016/j.jchemneu.2009.05.008. View

Kelly M, Levin E . Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab. 2001; 12(4):152-6. DOI: 10.1016/s1043-2760(01)00377-0. View

Shughrue P, Lane M, Merchenthaler I . Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997; 388(4):507-25. DOI: 10.1002/(sici)1096-9861(19971201)388:4<507::aid-cne1>3.0.co;2-6. View

Liang Y, Akishita M, Kim S, Ako J, Hashimoto M, Iijima K . Estrogen receptor beta is involved in the anorectic action of estrogen. Int J Obes Relat Metab Disord. 2002; 26(8):1103-9. DOI: 10.1038/sj.ijo.0802054. View

Tai M, Wang L, Wu K, Chan J . Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Radic Biol Med. 2005; 38(4):450-62. DOI: 10.1016/j.freeradbiomed.2004.11.015. View

10.

Shah A, Gul R, Yuan K, Gao S, Oh Y, Kim U . Angiotensin-(1-7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger. Am J Physiol Heart Circ Physiol. 2010; 298(5):H1365-74. DOI: 10.1152/ajpheart.00608.2009. View

11.

Saleh T, Connell B . 17beta-estradiol modulates baroreflex sensitivity and autonomic tone of female rats. J Auton Nerv Syst. 2000; 80(3):148-61. DOI: 10.1016/s0165-1838(00)00087-4. View

12.

Wang C, Shiau A, Chen S, Lin L, Tai M, Shieh G . Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. Arthritis Rheum. 2008; 58(6):1650-6. DOI: 10.1002/art.23517. View

13.

Simoncini T, Fornari L, Mannella P, Varone G, Caruso A, Liao J . Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase. Steroids. 2002; 67(12):935-9. DOI: 10.1016/s0039-128x(02)00040-5. View

14.

Saleh M, Connell B, Saleh T . Autonomic and cardiovascular reflex responses to central estrogen injection in ovariectomized female rats. Brain Res. 2000; 879(1-2):105-14. DOI: 10.1016/s0006-8993(00)02757-8. View

15.

Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M . Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels. Circulation. 1997; 96(6):1953-63. DOI: 10.1161/01.cir.96.6.1953. View

16.

Shughrue P, Merchenthaler I . Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol. 2001; 436(1):64-81. View

17.

Mohamed M, Abdel-Rahman A . Estrogen enhancement of baroreflex sensitivity is centrally mediated. Am J Physiol. 1999; 276(4):R1030-7. DOI: 10.1152/ajpregu.1999.276.4.R1030. View

18.

Pierce J, Kievits J, Graustein B, Speth R, Iadecola C, Milner T . Sex differences in the subcellular distribution of angiotensin type 1 receptors and NADPH oxidase subunits in the dendrites of C1 neurons in the rat rostral ventrolateral medulla. Neuroscience. 2009; 163(1):329-38. PMC: 2740659. DOI: 10.1016/j.neuroscience.2009.06.006. View

19.

Subramanian M, Balasubramanian P, Garver H, Northcott C, Zhao H, Haywood J . Chronic estradiol-17β exposure increases superoxide production in the rostral ventrolateral medulla and causes hypertension: reversal by resveratrol. Am J Physiol Regul Integr Comp Physiol. 2011; 300(6):R1560-8. PMC: 3119149. DOI: 10.1152/ajpregu.00020.2011. View

20.

Kuo T, Chan S . Continuous, on-line, real-time spectral analysis of systemic arterial pressure signals. Am J Physiol. 1993; 264(6 Pt 2):H2208-13. DOI: 10.1152/ajpheart.1993.264.6.H2208. View