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1 Pharmacology, University of Vermont, Burlington, Vermont, United States
2 Surgery, Division of Neurosurgery, University of Vermont, Burlington, Vermont, United States
3 Burlington, Vermont, United States; Surgery, Division of Neurosurgery, University of Vermont, Burlington, Vermont, United States
4 Pharmacology, University of Vermont, Burlington, Vermont, United States; Burlington, Vermont, United States; Surgery, Division of Neurosurgery, University of Vermont, Burlington, Vermont, United States
* To whom correspondence should be addressed. E-mail: George.Wellman{at}uvm.edu.
Oxyhemoglobin (OxyHb) can suppress voltage-dependent K+ channel (KV) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here, we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase epidermal growth factor receptor (EGFR) underlie OxyHb-induced KV channel suppression in the cerebral vasculature. Using the conventional whole-cell patch clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced KV suppression in rabbit cerebral artery myocytes. KV current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG 1478, but was unaffected by PKC inhibition. Compounds (heparin and CRM 197) that specifically interfere with HB-EGF signaling eliminated OxyHb-induced KV suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that when cleaved by matrix metalloproteases (MMPs) causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Further, the MMP inhibitor (GM 6001) abolished OxyHb-induced KV current suppression. We also observed KV current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to KV channel suppression. We propose that EGFR-mediated KV suppression contributes to vascular pathologies such as cerebral vasospasm and may play a more widespread role in the regulation of regional blood flow and peripheral resistance.
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