A growth factor mixture that significantly enhances angiogenesis in vivo

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)) de rived from bovine bone. The major components of GF(m) (SDS-polyacrylamide g el electrophoresis, mass spectrometry, and Western blot) include transformi ng growth factor-beta1-3, bone morphogenic protein-2-7, and fibroblast grow th factor-1. GF(m) was first shown to induce an angiogenic response in chor ioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (am eroid) 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 condition s) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 we eks later using quantitative and semiquantitative measures. There were GF, concentration-dependent improvements in distal left anterior descending art ery (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 vesse ls (P: 0.21 +/- 0.15,I: 1.00 +/- 0.22, II: 1.71 +/- 0.18, vascular growth s core p = 0.001). Resting myocardial blood flow (colored microspheres) was n ot significantly impaired in any group. However, maximum blood flow (adenos ine) was reduced in ischemic territories and did not improve in GF(m)-treat ed hearts. GF(m), a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not impr ove during maximal vasodilatory stress, large intramyocardial collateral ve ssels developed and angiographic visualization of the occluded distal LAD i mproved significantly. The use of multiple growth factors may be an effecti ve strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential .