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(Circulation Research. 2008;102:1275.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Heparin-Binding Epidermal Growth Factor–Like Growth Factor Signaling in Flow-Induced Arterial Remodeling

Hua Zhang, Susan W. Sunnarborg, K. Kirk McNaughton, Terrance G. Johns, David C. Lee, James E. Faber

From the Departments of Cell & Molecular Physiology (H.Z., K.K.M., J.E.F.) and Biochemistry & Biophysics (S.W.S.), University of North Carolina, Chapel Hill; Ludwig Institute for Cancer Research (T.G.J.), Heidelberg, Australia; and University of Georgia (D.C.L.), Athens.

Correspondence to James E. Faber, PhD, Department of Cell and Molecular Physiology, 6309 MBRB, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail jefaber{at}med.unc.edu

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 50% in HB-EGF^+/– and 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 –converting enzyme (pro-HB-EGF sheddase), increased phosphorylation of EGF receptor and extracellular signal-regulated kinase 1/2, and increased nuclear factor B activity. Apocynin and deletion of p47^phox inhibited FINR, whereas deletion of HB-EGF abolished nuclear factor 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.

Key Words: artery • flow-mediated remodeling • HB-EGF • reactive oxygen species • NF-B