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(Circulation Research. 2001;89:815.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Trophic Effect of Norepinephrine on Arterial Intima-Media and Adventitia Is Augmented by Injury and Mediated by Different 1-Adrenoceptor Subtypes

Hua Zhang, James E. Faber

From the Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC.

Correspondence to James E. Faber, PhD, Department of Cell and Molecular Physiology, 474 MSRB, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail jefaber{at}med.unc.edu

In vivo studies have suggested that norepinephrine (NE) directly contributes to normal vascular wall growth and worsening of hypertrophy, atherosclerosis, and restenosis. However, it is unknown whether these effects are secondary to hemodynamic changes caused by systemic NE or -adrenoceptor (AR) antagonists. Herein, we determined if NE directly stimulates growth of medial smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) that we have shown express 1-ARs in similar abundance. The rat aorta was isolated before injury, 4 days after, or 12 days after balloon injury, and maintained under circumferential tension in organ culture for 48 hours with 1 µmol/L NE. Intima-media and adventitia were separated and DNA content, protein synthesis, and protein content measured. In uninjured aorta, NE increased DNA and protein content similarly in adventitia, and increased only protein content in intima-media, suggesting AFB proliferation and SMC hypertrophy. In vessels isolated 4 or 12 days after injury, NE increased all 3 endpoints in both layers by up to 20-fold greater than in uninjured vessels. These effects were dose-dependent and were unaffected by 2- or ß-AR blockade (except increased DNA content in adventitia that was also inhibited by 2-AR blockade). Intima-media growth was blocked by KMD3213 (1A-AR antagonist) and adventitial growth by AH11110A (1B-AR antagonist), whereas BMY7378 (1D-AR antagonist) had no effect. NE decreased SMC marker proteins (eg, -smooth muscle actin and desmin) and augmented the changes induced by injury. These data suggest that prolonged stimulation of 1A- and 1B-ARs induces growth of SMCs and AFBs, respectively, that is significantly augmented by injury.

Key Words: artery • smooth muscle cell • adventitial fibroblast • growth • organ culture

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