Abstract 1165: Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates Low Flow-Induced Negative Hypertrophic Remodeling (FINR) But Not High Flow-Induced Positive Eutrophic Remodeling (FIPR) of Carotid Artery
HB-EGF has been implicated in physiological and pathological processes, eg, heart valve development, wound healing, vascular smooth muscle proliferation, and it is upregulated in atherosclerosis and restenosis. Herein we studied the role of HB-EGF in flow-mediated remodeling. The left internal and external carotid and occipital arteries, but not thyroid artery, were ligated in mice. Common carotid arteries were harvested 21 days later and analyzed in blinded fashion. FINR of left carotid consisted of lumen narrowing, intima-media and adventitia thickening, and increased circumference of the external elastic laminus (EEL) (Table 1⇓). FINR was almost completely inhibited in HB-EGF−/−. The known cardiac hypertrophy of HB-EGF−/− had not progressed to heart failure and did not correlate with inhibition of FINR. Moreover, FINR was partially inhibited in HB-EGF+/− and also in wildtype mice chronically treated with EGFR antagonist AG1478-mesylate (346ug/day), yet neither group had cardiac hypertrophy. Immunoblot analysis of left carotid after ligation found that ADAM-17 increased 2-fold at 12h and 36h, phospho-EGFR increased 2-fold at 36h, and phospho-ERK increased 7-, 9- and 9-fold at 12h, 36h and 5 days. Immunohistochemistry found increased CD45-positive leukocytes on endothelium and in intimamedia and adventitia 5 days after ligation. This increase was inhibited in HB-EGF−/− in intima-media and adventitia but not on endothelium (6.3% vs. 1.3%, 26.1% vs.11.2%, p < 0.05; but 7.5% vs. 9.3%). FIPR of right carotid was not affected in any of the treatment groups. These findings suggest that low flow-induced negative hypertrophic remodeling is strongly dependent on HB-EGF signaling.