期刊
CIRCULATION RESEARCH
卷 102, 期 10, 页码 1275-1285出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.171728
关键词
artery; flow-mediated remodeling; HB-EGF; reactive oxygen species; NF-kappa B
资金
- NCI NIH HHS [CA43793, R01 CA043793] Funding Source: Medline
- NHLBI NIH HHS [HL62584, R01 HL062584-11, R01 HL062584] Funding Source: Medline
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 approximate to 50% in HB-EGF(+/-) and approximate to 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 kappa B activity. Apocynin and deletion of p47(phox) inhibited FINR, whereas deletion of HB-EGF abolished nuclear factor kappa B 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.
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