2-methoxyestradiol induces vasodilation by stimulating NO release via PPARγ/PI3K/Akt pathway.
The endogenous estradiol metabolite 2-methoxyestradiol (2-ME) reduces atherosclerotic lesion formation, while the underlying mechanisms remain obscure. In this work, we investigated the vasodilatory effect of 2-ME and the role of nitric oxide (NO) involved. In vivo studies using noninvasive tail-cuff methods showed that 2-ME decreased blood pressure in Sprague Dawley rats. Furthermore, in vitro studies showed that cumulative addition of 2-ME to the aorta caused a dose- and endothelium-dependent vasodilation. This effect was unaffected by the pretreatment with the pure estrogen receptor antagonist ICI 182,780, but was largely impaired by endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (WM). Moreover, 2-ME（10-7 ∼10-5 M）enhanced phosphorylation of Akt and eNOS and promoted NO release from cultured human umbilical endothelial cells (HUVECs). These effects were blocked by PI3K inhibitor WM, or by the transfection with Akt specific siRNA, indicating that endothelial Akt/eNOS/NO cascade plays a crucial role in 2-ME-induced vasodilation. The peroxisome proliferator-activated receptor γ (PPARγ) mRNA and protein expression were detected in HUVECs and the antagonist GW9662 or the transfection with specific PPARγ siRNA inhibited 2-ME-induced eNOS and Akt phosphorylation, leading to the impairment of NO production and vasodilation. In conclusion, 2-ME induces vasodilation by stimulating NO release. These actions may be mediated by PPARγ and the subsequent activation of Akt/eNOS cascade in vascular endothelial cells.
School of Basic Sciences, Guangzhou Medical University, Guangzhou, 510182, Guangdong Province, China; Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China.
Weiyu
W
Chen
School of Basic Sciences, Guangzhou Medical University, Guangzhou, 510182, Guangdong Province, China.
Yuhong
Y
Cui
Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong Province, China.
Shuhui
S
Zheng
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China.
Jinghe
J
Huang
School of Basic Sciences, Guangzhou Medical University, Guangzhou, 510182, Guangdong Province, China.
Ping
P
Li
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, 56100, Italy.
Tommaso
T
Simoncini
Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou, 510180, Guangdong Province, China.
Yongfu
Y
Zhang
School of Basic Sciences, Guangzhou Medical University, Guangzhou, 510182, Guangdong Province, China.
Xiaodong
X
Fu
D000077584:2-Methoxyestradiol; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
D047495:PPAR gamma; D009569:Nitric Oxide; D004958:Estradiol; D000077584:2-Methoxyestradiol; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt