EGFR transactivation in the regulation of SMC function.
Vascular smooth muscle cells (SMCs) are the principal cellular component of the normal artery and intimal lesions that develop in response to arterial injury. Several growth factors and their receptors participate in SMC activation, including the tyrosine kinase receptors for platelet-derived growth factor (PDGF) and basic fibroblast growth factor as well as the G-protein-coupled receptors (GPCRs) for thrombin and angiotensin II. During the last couple of years, it has become evident that GPCRs transactivate receptor tyrosine kinases, particularly the epidermal growth factor receptor (EGFR). The EGFR is not well characterized in terms of its role in vascular biology, but recent findings indicate that GPCRs induce EGFR transactivation in cultured vascular SMCs, perhaps by intracellular and extracellular pathways. Studies from our laboratory as well as two other groups have demonstrated that EGFR transactivation by different GPCR agonists and in different cell types, including SMCs, is mediated by heparin-binding EGF-like growth factor (HB-EGF). HB-EGF-dependent EGFR activation is blocked by heparin, a growth inhibitor of SMCs in vitro and in vivo. These data suggest that the EGFR may be important in the regulation of SMC function. The complexity of the GPCR-EGFR crosstalk, involving several different cell surface molecules and an inside-out signaling step, may provide novel targets for the control of SMC growth and intimal hyperplasia in the arterial injury response.
Kalmes
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Department of Surgery, University of Washington, Seattle 98195-6410, USA.
Daum
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Clowes
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D000818:Animals; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013917:Thrombin / Q000502:physiology; D015533:Transcriptional Activation; D017539:Tunica Intima / Q000166:cytology / Q000502:physiology
D006133:Growth Substances; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D013917:Thrombin