A more recent version of this article appeared on October 1, 2006

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:e133.)
© 2006 American Heart Association, Inc.

Vascular Biology

ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II

Haruhiko Ohtsu; Peter J. Dempsey; Gerald D. Frank; Eugen Brailoiu; Sadaharu Higuchi; Hiroyuki Suzuki; Hidekatsu Nakashima; Kunie Eguchi; Satoru Eguchi

From the Cardiovascular Research Center (H.O., S.H., H.S., H.N., K.E., S.E.) and Departments of Physiology (H.O., S.H., H.S., H.N., K.E., S.E.) and Pharmacology (E.B.), Temple University School of Medicine. Philadelphia, Pa; the Departments of Pediatrics and Molecular and Integrative Physiology (P.J.D.), University of Michigan, Ann Arbor, Mich; and the Department of Biochemistry (G.D.F.), Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Satoru Eguchi, MD, PhD, FAHA, Cardiovascular Research Center, Temple University School of Medicine, 3420 N. Broad St, Philadelphia, PA 19140. E-mail seguchi{at}temple.edu

Background— Angiotensin II (Ang II) promotes growth of vascular smooth muscle cells (VSMCs) via epidermal growth factor (EGF) receptor (EGFR) transactivation mediated through a metalloprotease-dependent shedding of heparin-binding EGF-like growth factor (HB-EGF). However, the identity of the metalloprotease responsible for this process remains unknown.

Methods and Results— To identify the metalloprotease required for Ang II-induced EGFR transactivation, primary cultured aortic VSMCs were infected with retrovirus encoding dominant negative (dn) mutant of ADAM10 or ADAM17. EGFR transactivation induced by Ang II was inhibited in VSMCs infected with dnADAM17 retrovirus but not with dnADAM10 retrovirus. However, Ang II comparably stimulated intracellular Ca²⁺ elevation and JAK2 tyrosine phosphorylation in these VSMCs. In addition, dnADAM17 inhibited HB-EGF shedding induced by Ang II in A10 VSMCs expressing the AT₁ receptor. Moreover, Ang II enhanced protein synthesis and cell volume in VSMCs infected with control retrovirus, but not in VSMCs infected with dnADAM17 retrovirus.

Conclusion— ADAM17 activated by the AT₁ receptor is responsible for EGFR transactivation and subsequent protein synthesis in VSMCs. These findings demonstrate a previously missing molecular mechanism by which Ang II promotes vascular remodeling.

By using vascular smooth muscle cells, we demonstrate that a metalloprotease ADAM17 is responsible for epidermal growth factor receptor transactivation and subsequent protein synthesis induced by angiotensin II. The findings demonstrate a previously missing molecular mechanism by which angiotensin II promotes vascular hypertrophy.

Key Words: AT₁ receptor • metalloprotease • HB-EGF • signal transduction

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