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Symposium related papers |
Departments of
1 Neurosurgery
2 Pathology
3 Physiology, University of Maryland at Baltimore, Baltimore, MD 21201, USA
Abstract
In synthetic phenotype vascular smooth muscle cells (VSMC), activation of epidermal growth factor (EGF) receptor (EGFR) induces a sustained increase in intermediate conductance KCa (int-KCa; KCa3.1) channels that is essential for proliferation. However, a comparable mechanism has not been identified in native contractile phenotype VSMC, which express large conductance KCa (maxi-KCa; KCa1.1) channels, not int-KCa channels. Using patch clamp of freshly isolated contractile VSMC from rat basilar artery, we found that EGF (100 ng ml–1) caused hyperpolarization (7.9 ± 3.9 mV) due to activation of iberiotoxin-sensitive, maxi-KCa channels. The EGFR ligands EGF (100 ng ml–1), transforming growth factor 
(0.4 ng ml–1) and heparin-binding EGF (100 ng ml–1) all caused a 20% increase in maxi-KCa channel current that was blocked by AG-1478 or by knock-down of EGFR expression using cisterna magna infusion of antisense oligodeoxynucleotide (AS-ODN). In controls, EGFR knock-down, and EGFR gain-of-expression (angiotensin II hypertension), the increase in maxi-KCa current correlated with the abundance of EGFR protein expressed. The EGFR-mediated increase in maxi-KCa channel activity was blocked by inhibiting cAMP-dependent protein kinase (cAK) using KT-5720 or Rp-cAMP, or by inhibiting adenylate cyclase type 5 (AC-5) using 2',5'-dideoxyadenosine or knock-down of AC-5 expression by intracisternal AS-ODN. Direct infusion of EGF into cisterna magna caused up-regulation of proliferating cell nuclear antigen (PCNA) in VSMC that was prevented by coinfusion of iberiotoxin or of AG-1478. Our data, which are consistent with the hypothesis that hyperpolarization is critical for a proliferative response, are the first to implicate AC-5 and maxi-KCa channels in gene activation related to EGFR signalling in native contractile VSMC.
(Received 27 October 2005;
accepted after revision 10 November 2005;
first published online 10 November 2005)
Corresponding author J. M. Simard: Department of Neurosurgery, 22 S. Greene Street, Suite 12SD, Baltimore, MD 21201-1595, USA. Email: msimard{at}surgery1.umaryland.edu
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