Cell Replication in the Arterial Wall

Activation of Signaling Pathway Following In Vivo Injury

From the Department of Pathology, University of Washington, Seattle.

Correspondence to Michael A. Reidy, PhD, Department of Pathology/Vascular Biology, Box 357335, University of Washington, Seattle, WA 98195-7335. E-mail mar1{at}u.washington.edu

Abstract—This study examined intracellular signal events of arterial cells following balloon catheter injury to rat carotid artery. Within 30 minutes, a marked increase in extracellular signal–regulated kinase-1/2 (ERK1/2) activity was observed. This activity remained elevated for 12 hours but had decreased to control levels by day 1. No increase in ERK1/2 was detected at any later times. Injection of anti–fibroblast growth factor 2 antibody (60 mg IV) significantly inhibited the activation of ERK1/2 at 30 minutes after the injury. PD98059 (80 µmol/L), a selective inhibitor of mitogen-activated protein kinase/ERK kinase-1 (MEK1), decreased ERK1/2 activity in injured arteries and also reduced the medial cell replication. In contrast, PD98059 did not block the intimal cell replication at day 8. Mitogen-activated protein kinase phosphatase-1 (MKP-1) was expressed within hours after injury but only weakly at later times; MKP-1 was again expressed after 7 and 14 days. The expression of MKP-1 was associated with an activation of c-Jun amino-terminal kinase. Injury to the arterial wall also stimulated the activity of p70 S6 kinase from 30 minutes to 12 hours, suggesting an alternative pathway in mitogenic signaling of early cell replication. These findings demonstrate that fibroblast growth factor 2–induced ERK1/2 activation promotes medial cell replication after balloon injury; however, signaling of intimal cell replication may not be linked to the MEK1-dependent ERK pathway.

Key Words: balloon injury • cell replication • extracellular signal–regulated kinase-1/2 • mitogen-activated protein kinase phosphatase-1 • p70 S6 kinase

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