Cell Replication in the Arterial Wall

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 i.v.) significantly inhibited the activation of ERK1/2 at 30 minutes after the injury. PD98059 (80 micromol/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.

Central role of RAGE-dependent neointimal expansion in arterial restenosis

“…In mice treated with sRAGE, however, no suppression of phosphorylation of Erk1/2 or PKB was observed ( Figure 4, c and d). Previous work has shown that pharmacologic blockade of mitogenactivated protein kinase-1 or PI3K suppressed an early phase of medial cell proliferation, but was without effect on intimal proliferation, the latter contributing centrally to restenosis in rodent models (42,43). A recent study, however, demonstrated activation of Jak2 and Stat3 (as well as more transient activation of Stat1) following arterial injury (45).…”

“…phase of cellular proliferation in the repairing arterial segment (42,43). To study these cascades, phosphorylation of Erk1/2 and protein kinase B (PKB), the latter a downstream target of PI3K (44), was assessed.…”

Isoproterenol Inhibits Angiotensin II-Stimulated Proliferation and Reactive Oxygen Species Production in Vascular Smooth Muscle Cells through Heme Oxygenase-1

“…The ERK1/2 pathway is a tyrosine kinase-dependent pathway normally stimulated by growth factor receptors that are involved in cell growth, proliferation and differentiation. Ang II also activates c-src dependent mechanism 16) and c-src was suggested to control VSMCs proliferation 17) and vascular contraction. 18) Treatment with an MEK-1 inhibitor PD98059 reduced Ang II-induced high blood pressure in vivo 19) and prevented the contractile effects of Ang II in isolated resistance arteries in vitro.…”

Cudratricusxanthone A Isolated from the Root Bark of Cudrania tricuspidata Inhibits the Proliferation of Vascular Smooth Muscle Cells through the Suppression of PDGF-Receptor Beta Tyrosine Kinase

“…7) Using balloon injured carotid artery, it was demonstrated that MAPK signaling, especially ERK1/2, is increased and that medial cell replication following injury is reduced by PD098059. 13) ERK1/2 (a MAPK family member) plays a central role on cell growth regulation, and recently this pathway was found to be involved by triggering Ras-Raf activation, MEK phosphorylation, and ERK1/2 phosphorylations in the proliferative effect of PDGF-BB in VSMCs. 6,7,11,14) As shown in Fig.…”