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(Hypertension. 2002;39:41.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Estrogen Activates Phosphatases and Antagonizes Growth-Promoting Effect of Angiotensin II

Yuko Takeda-Matsubara; Hironori Nakagami; Masaru Iwai; Tai-Xing Cui; Tetsuya Shiuchi; Masahiro Akishita; Clara Nahmias; Masaharu Ito; Masatsugu Horiuchi

From the Departments of Medical Biochemistry (Y.T.-M., H.N., M.I., T.-X.C., T.S., M.H.) and Obstetrics and Gynecology (Y.T.-M., M.I.), Ehime University School of Medicine, Ehime, Japan; Department of Geriatric Medicine, Kyorin University School of Medicine (M.A.), Tokyo, Japan; and CNRS UPR0415-Institut Cochin de Genetique Moleculaire (C.N.), Paris, France.

Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Accumulating evidence suggests that estrogen exerts cardioprotective effects and protects against neointima formation in response to vascular injury in vivo, whereas angiotensin (Ang) II stimulation via the Ang II type 1 (AT₁) receptor exaggerates vascular injury. We postulate that estrogen treatment antagonizes the AT₁ receptor-mediated growth-promoting effects in vascular smooth muscle cells (VSMCs). The present in vitro study was designed to explore this possibility and to establish the cellular mechanism whereby estrogen attenuates the growth of VSMCs. Primary cultures of VSMCs derived from male adult Sprague-Dawley rats express exclusively AT₁ receptors. Treatment with Ang II enhanced proliferation of VSMC and c-fos expression, whereas 17ß-estradiol (E2) attenuated these vasotrophic effects of Ang II. We also demonstrated that E2 attenuated AT₁ receptor-mediated extracellular signal-regulated kinase activation and that this effect of E2 was restored by pretreatment with vanadate or okadaic acid. Moreover, we demonstrated that E2 enhanced SHP-1 activity, rapidly reaching a peak after 3 minutes of E2 stimulation, whereas E2 transactivated mitogen-activated protein kinase phosphatase-1 expression, showing a peak after 60 minutes of E2 treatment. SHP-1 activation was not influenced by actinomycin D treatment, whereas E2-mediated mitogen-activated protein kinase phosphatase-1 expression was attenuated. Taken together, our results suggest a novel mechanism of vasoprotection by which estrogen antagonizes the effect of the AT₁ receptor via the activation and induction of phosphatases through nongenomic as well as genomic signaling.

Key Words: angiotensin II • estrogen • receptors, angiotensin II • signal transduction • vasculature

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