Vol. 299, Issue 2, 494-500, November 2001

A Growth Factor Mixture That Significantly Enhances Angiogenesis in Vivo

Wilfried Roethy, Eduard Fiehn, Kotaro Suehiro, Anguo Gu, Geng Hua Yi, Juichiro Shimizu, Jie Wang, Geping Zhang, John Ranieri, Rama Akella, Sarah E. Funk, E. Helene Sage, James Benedict and Daniel Burkhoff

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York (W.R., E.F., K.S., A.G., G.H.Y., J.S., J.W., G.Z., D.B.); Sulzer Inc., Austin, Texas (J.R., R.A., J.B.); and Hope Heart Institute, Seattle, Washington (S.E.F., E.H.S.)

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 (GF_m) derived from bovine bone. The major components of GF_m (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-1-3, bone morphogenic protein-2-7, and fibroblast growth factor-1. GF_m was 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 GF_m 1 mg/ml (I), GF_m 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 GF_m concentration-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 score p = 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 GF_m-treated hearts. GF_m, 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.