Abstract
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.
Footnotes
-
This study was supported by a grant from Sulzer Medica, Inc. (Austin, TX).
- Abbreviations:
- VEGF
- vascular endothelial growth factor
- bFGF
- basic fibroblast growth factor
- HPLC
- high-pressure liquid chromatography
- IBP
- inactive bone protein
- PAGE
- polyacrylamide gel electrophoresis
- CAM
- chorioallantoic membranes
- GFm
- growth factor mixture
- Df
- fractal dimension
- LAD
- left anterior descending artery
- BrdU
- bromodeoxyuridine
- CMS
- colored microspheres
- Received May 30, 2001.
- Accepted August 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|