title: Heparin-binding epidermal growth factor-like growth factor signaling in flow-induced arterial remodeling.
abstract: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is activated by reduced endothelial shear stress and stimulates smooth muscle cell proliferation in vitro. Moreover, HB-EGF is augmented at sites of intimal hyperplasia and atherosclerosis, conditions favored by low/disturbed shear stress. We thus tested whether HB-EGF contributes to low flow-induced negative hypertrophic remodeling (FINR) of a mouse carotid artery. Blood flow was surgically decreased in the left and increased in the right common carotid arteries. After 21 days, the left carotid artery exhibited lumen narrowing, thickening of intima-media and adventitia, and increased circumference that were inhibited by approximately 50% in HB-EGF(+/-) and approximately 90% in HB-EGF(-/-) mice. FINR was also inhibited by the EGF receptor inhibitor AG1478. In contrast, eutrophic outward remodeling of the right carotid artery was unaffected in HB-EGF(+/-) and HB-EGF(-/-) mice, nor by AG1478. FINR-induced proliferation and leukocyte accumulation were reduced in HB-EGF(-/-). FINR was associated with increased reactive oxygen species, increased expression of pro-HB-EGF and tumor necrosis factor alpha-converting enzyme (pro-HB-EGF sheddase), increased phosphorylation of EGF receptor and extracellular signal-regulated kinase 1/2, and increased nuclear factor kappaB activity. Apocynin and deletion of p47(phox) inhibited FINR, whereas deletion of HB-EGF abolished nuclear factor kappaB activation in smooth muscle cells. These findings suggest that HB-EGF signaling is required for low flow-induced hypertrophic remodeling and may participate in vascular wall disease and remodeling.
authors.affiliation: Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599-7545, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Susan W
authors.initials: SW
authors.lastname: Sunnarborg
authors.forename: K Kirk
authors.initials: KK
authors.lastname: McNaughton
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: David C
authors.initials: DC
authors.lastname: Lee
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000473:pathology / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3