RT Journal Article
SR Electronic
T1 A Growth Factor Mixture That Significantly Enhances Angiogenesis in Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 494
OP 500
VO 299
IS 2
A1 Wilfried Roethy
A1 Eduard Fiehn
A1 Kotaro Suehiro
A1 Anguo Gu
A1 Geng Hua Yi
A1 Juichiro Shimizu
A1 Jie Wang
A1 Geping Zhang
A1 John Ranieri
A1 Rama Akella
A1 Sarah E. Funk
A1 E. Helene Sage
A1 James Benedict
A1 Daniel Burkhoff
YR 2001
UL http://jpet.aspetjournals.org/content/299/2/494.abstract
AB Studies of therapeutic angiogenesis have generally focused on single growth factor strategies. However, multiple factors participate in angiogenesis. We evaluated the angiogenic potential of a growth factor mixture (GFm) derived from bovine bone. The major components of GFm (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-β1–3, bone morphogenic protein-2–7, and fibroblast growth factor-1. GFmwas first shown to induce an angiogenic response in chorioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (ameroid) that were randomized 3 weeks later to received GFm 1 mg/ml (I), GFm 10 mg/ml (II), or placebo (P) (with investigators blinded to conditions) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 weeks later using quantitative and semiquantitative measures. There were GFmconcentration-dependent improvements in distal left anterior descending artery (LAD) opacification by angiography (P: 0.4 ± 0.2, I: 1.1 ± 0.14, II: 1.6 ± 0.3, angiographic scorep = 0.014). Histologically, there was also concentration-dependent vascular growth response of relatively large vessels (P: 0.21 ± 0.15, I: 1.00 ± 0.22, II: 1.71 ± 0.18, vascular growth score p = 0.001). Resting myocardial blood flow (colored microspheres) was not significantly impaired in any group. However, maximum blood flow (adenosine) was reduced in ischemic territories and did not improve in GFm-treated hearts. GFm, a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not improve during maximal vasodilatory stress, large intramyocardial collateral vessels developed and angiographic visualization of the occluded distal LAD improved significantly. The use of multiple growth factors may be an effective strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential. The American Society for Pharmacology and Experimental Therapeutics