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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1884.)
© 2005 American Heart Association, Inc.

Vascular Biology

Heparin-Binding Epidermal Growth Factor–Like Growth Factor, Collateral Vessel Development, and Angiogenesis in Skeletal Muscle Ischemia

Dan Chalothorn; Scott M. Moore; Hua Zhang; Susan W. Sunnarborg; David C. Lee; James E. Faber

From the Departments of Cell and Molecular Physiology (D.C., S.M.M., H.Z., J.E.F.) and Biochemistry (S.W.S., D.C.L.), University of North Carolina, Chapel Hill.

Correspondence to James E. Faber, PhD, Dept of Cell and Molecular Physiology, 103 Mason Farm Rd, 6309 MBRB, CB 7545, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail jefaber{at}med.unc.edu

Objective— Heparin-binding epidermal growth factor–like growth factor (HB-EGF) is a potent mitogen for smooth muscle cells and has been implicated in atherosclerosis, tissue regeneration after ischemia, vascular development, and tumor angiogenesis. We examined the hypothesis that HB-EGF participates in angiogenesis and collateral growth in ischemia.

Methods and Results— During 3 weeks after femoral artery ligation, no attenuation occurred in recovery of hindlimb perfusion or distal saphenous artery flow in HB-EGF–null (HB-EGF^–/–) versus wild-type mice. Lumen diameters of remodeled collaterals in gracilis muscle were similar by morphometry (87±8 versus 94±6 µm) and angiography, although medial thickening was reduced. Gastrocnemius muscle underwent comparable angiogenesis (41% and 33% increase in capillary-to-muscle fiber ratio). Renal renin mRNA, arterial pressure, and heart rate during anesthesia or conscious unrestrained conditions were similar between groups. These latter findings validate comparisons of perfusion data and also suggest that differences in arterial pressure and/or renin–angiotensin activity are not masking an otherwise inhibitory effect of HB-EGF absence. Four days after ligation, EGF receptor phosphorylation increased in muscle by 104% in wild-type but by only 30% in HB-EGF^–/– mice. This argues against compensation by other EGF receptor ligands.

Conclusion— Our results suggest that HB-EGF is not required for arteriogenesis or angiogenesis in hindlimb ischemia.

We examined whether HB-EGF participates in arteriogenesis and angiogenesis after femoral ligation in HB-EGF-null (^–/–) mice. No attenuation occurred in hind-limb perfusion recovery, collateral growth, or angiogenesis. Renin and arterial pressure were unaltered in HB-EGF^–/–. Although EGFR phosphorylation was decreased in HB-EGF^–/–, HB-EGF is not required for arteriogenesis or angiogenesis.

Key Words: angiogenesis • collateral formation • HB-EGF

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