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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2002-01, Vol.39 (1), p.41-45
• Main Authors: Takeda-Matsubara, Yuko, Nakagami, Hironori, Iwai, Masaru, Cui, Tai-Xing, Shiuchi, Tetsuya, Akishita, Masahiro, Nahmias, Clara, Ito, Masaharu, Horiuchi, Masatsugu
• Format: Article
• Language: English
• Subjects: Angiotensin II - antagonists & inhibitors; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Biological and medical sciences; Cell Cycle Proteins; Cell Division - drug effects; Cell Division - physiology; Cells, Cultured; Drug Interactions; Dual Specificity Phosphatase 1; Enzyme Activation - drug effects; Estradiol - pharmacology; Hormones. Endocrine system; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Intracellular Signaling Peptides and Proteins; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Pharmacology. Drug treatments; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - biosynthesis; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk - drug effects; Receptor Cross-Talk - physiology; Receptor, Angiotensin, Type 1; Receptors, Angiotensin - physiology; Receptors, Estrogen - physiology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hy1201.097197

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 17β-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.