Original Article2-Methoxyestradiol Attenuates Angiotensin II-Induced Hypertension, Cardiovascular Remodeling, and Renal InjurySalah, Eman MD*,†; Bastacky, Sheldon I. MD†; Jackson, Edwin K. PhD*; Tofovic, Stevan P. MD, PhD*,‡Author Information Departments of *Pharmacology and Chemical Biology; and †Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and ‡Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA. Reprints: Stevan P. Tofovic, MD, PhD, Department of Pharmacology and Chemical Biology, Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, 100 Technology Drive, Room 542, Pittsburgh, PA 15219 (e-mail: [email protected]). The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: March 2019 - Volume 73 - Issue 3 - p 165-177 doi: 10.1097/FJC.0000000000000649 Buy Metrics Abstract Estradiol may antagonize the adverse cardiovascular effects of angiotensin II (Ang II). We investigated the effects of 2-methoxyestradiol (2-ME), a nonestrogenic estradiol metabolite, on Ang II-induced cardiovascular and renal injury in male rats. First, we determined the effects of 2-ME on Ang II-induced acute changes in blood pressure, renal hemodynamics, and excretory function. Next, we investigated the effects of 2-ME and 2-hydroxyestardiol (2-HE) on hypertension and cardiovascular and renal injury induced by chronic infusion of Ang II. Furthermore, the effects of 2-ME on blood pressure and cardiovascular remodeling in the constricted aorta (CA) rat model and on isoproterenol-induced (ISO) cardiac hypertrophy and fibrosis were examined. 2-ME had no effects on Ang II-induced acute changes in blood pressure, renal hemodynamics, or glomerular filtration rate. Both 2-ME and 2-HE reduced hypertension, cardiac hypertrophy, proteinuria, and mesangial expansion induced by chronic Ang II infusions. In CA rats, 2-ME attenuated cardiac hypertrophy and fibrosis and reduced elevated blood pressure above the constriction. Notably, 2-ME reduced both pressure-dependent (above constriction) and pressure-independent (below constriction) vascular remodeling. 2-ME had no effects on ISO-induced renin release yet reduced ISO-induced cardiac hypertrophy and fibrosis. This study shows that 2-ME protects against cardiovascular and renal injury due to chronic activation of the renin–angiotensin system. This study reports for the first time that in vivo 2-ME reduces trophic (pressure-independent) effects of Ang II and related cardiac and vascular remodeling. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.