Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury

Pang-Yen Liu; Nobuaki Fukuma; Yukio Hiroi; Akiko Kunita; Hiroyuki Tokiwa; Kazutaka Ueda; Taro Kariya; Genri Numata; Yusuke Adachi; Miyu Tajima; Masayuki Toyoda; Yuxin Li; Kensuke Noma; Mutsuo Harada; Haruhiro Toko; Tetsuo Ushiku; Yoshimitsu Kanai; Eiki Takimoto; James K Liao; Issei Komuro

doi:10.1016/j.jacbts.2022.07.001

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury

JACC Basic Transl Sci. 2022 Nov 16;8(1):55-67. doi: 10.1016/j.jacbts.2022.07.001. eCollection 2023 Jan.

Authors

Pang-Yen Liu^{1

2}, Nobuaki Fukuma², Yukio Hiroi^{3

4}, Akiko Kunita⁵, Hiroyuki Tokiwa², Kazutaka Ueda², Taro Kariya^{2

6}, Genri Numata², Yusuke Adachi², Miyu Tajima², Masayuki Toyoda², Yuxin Li^{4

7}, Kensuke Noma^{4

8}, Mutsuo Harada², Haruhiro Toko², Tetsuo Ushiku⁵, Yoshimitsu Kanai⁹, Eiki Takimoto^{2

10}, James K Liao^{4

11}, Issei Komuro²

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital Penghu Branch, National Defense Medical Center, Taipei, Taiwan.
² Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ National Center for Global Health and Medicine, Tokyo, Japan.
⁴ Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
⁵ Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁶ Department of Anesthesiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁷ Nihon University School of Medicine, Tokyo, Japan.
⁸ Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
⁹ Department of Anatomy and Cell Biology, Wakayama Medical University, School of Medicine, Wakayama, Japan.
¹⁰ Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
¹¹ Section of Cardiology, Department of Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.

Abstract

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.

Keywords: E2, 17β-estradiol; ECGM, endothelial cell growth medium; ER, estrogen receptor; ERαKI/KI, estrogen receptor-αknock-in/knock-in; LVEDD, left ventricular end-diastolic diameter; NOS, nitric oxide synthase; PI3K, phosphatidylinositol 3-kinase; PLA, proximity ligation assay; Vo2, oxygen consumption; cDNA, complementary deoxyribonucleic acid; eNOS, endothelial nitric oxide synthase; endothelial cells; estrogen receptor-α; non-nuclear signaling; tissue-specific regulation.

Grants and funding

R01 HL136962/HL/NHLBI NIH HHS/United States