Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR.
We showed previously that vascular smooth muscle cells (VMSC) from spontaneously hypertensive rats (SHR) exhibit increased proliferation. The present study was undertaken to examine whether the enhanced levels of endogenous angiotensin (ANG) II and endothelin (ET)-1 contribute to the enhanced proliferation of VSMC from SHR and to further investigate the underlying mechanisms responsible for this response. The enhanced proliferation of VSMC from SHR compared with Wistar-Kyoto (WKY) rats was attenuated by losartan, BQ-123, BQ-788, and AG-1478, inhibitors of AT(1), ET(A), ET(B) and epidermal growth factor (EGF-R) receptors, respectively. In addition, BQ-123 and BQ-788 also attenuated the enhanced production of superoxide anion (O(2)(-)) and NADPH oxidase activity. Furthermore, diphenyleneiodonium (DPI, inhibitor of NADPH oxidase), N-acetyl-L-cysteine (NAC, O(2)(-) scavenger), and PP2 (inhibitor of c-Src) also inhibited the augmented proliferation of VSMC from SHR to WKY levels. In addition, the enhanced phosphorylation of EGF-R in VSMC from SHR compared with WKY was also attenuated by inhibitors of AT(1), ET(A), ET(B), and EGF-R but not by inhibitors of platelet-derived growth factor receptor or insulin-like growth factor receptor. Furthermore, the enhanced phosphorylation of ERK1/2 in VSMC from SHR was also attenuated by AT(1), ET(A), ET(B), c-Src, and EGF-R inhibitors. The phosphorylation of c-Src was significantly augmented in VSMC from SHR compared with VSMC from WKY and was attenuated by DPI and NAC. These data suggest that endogenous vasoactive peptides, through increased oxidative stress and resultant activation of c-Src, transactivate EGF-R, which through mitogen-activated protein (MAP) kinase signaling may contribute to the hyperproliferation of VSMC from SHR.
Li
Yuan
Y
Department of Physiology, Faculty of Medicine, University of Montreal, Montréal, Québec, Canada.
Lévesque
Louis-Olivier
LO
Anand-Srivastava
Madhu B
MB
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006965:Hyperplasia; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D019061:src-Family Kinases
D047228:Angiotensin II Type 1 Receptor Blockers; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013481:Superoxides; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D019255:NADPH Oxidases; C483803:Egfr protein, rat; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases