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A bone-derived mixture of TGFβ-superfamily members forms a more mature vascular network than bFGF or TGF-β2 in vivo

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Abstract

Clinical trials of therapeutic angiogenesis for the treatment of cardiovascular ischemia have failed to meet the expectations with the use of single growth factors, namely VEGF and bFGF. We show here that a bovine bone-derived growth factor mixture (GFM) of TGFβs, BMPs, and no more than 0.1% aFGF can initiate a dose-dependent angiogenic response in subcutaneously implanted Growth Factor Reduced Matrigel plugs that includes abundant smooth muscle actin positive (SMA+) tubes and functional CD31+, red blood cell filled, capillaries. Tube forming activity of the single factors, recombinant bFGF and bone-derived TGF-β2, were comparable to GFM, but only the bone-derived factors were able to create a larger fraction of SMA+ tubes than Matrigel alone at an equal dose. Basic FGF formed a greater number of RBC-filled capillaries within the plugs than GFM or TGF-β2 at the highest doses, although GFM created RBC-filled capillaries that penetrated deeper into the plugs than bFGF. However, bFGF showed the greatest number of non-cell-lined, RBC-filled pools, suggestive of vessel rupture, and the largest number of plugs showing signs of fluid accumulation in the form of large, cell-lined clefts in the implants. TGF-β2 showed less RBC-filled pools, but a significant number of implants with signs of fluid accumulation. At high doses of GFM penetration by blood vessels and mesenchymal cells was obstructed by cartilage development within the plugs accompanied by a prominent band of SMA+ granulation tissue with abundant RBC-filled capillaries encapsulating the implants. Thus, GFM is also capable of dramatically remodeling the vascular system in the interstitial space surrounding the plug. These results show that GFM is capable of inducing the formation of a more mature vascular system than that formed by the single factors bFGF and TGFβ-2. Natural mixtures of TGFβs, BMPs, and FGFs may have superior clinical utility in therapeutic angiogenesis applications.

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Abbreviations

aFGF:

acidic fibroblast growth factor

bFGF:

basic fibroblast growth factor

BMP:

bone morphogenetic protein

GFM:

growth factor mixture

GFR Matrigel:

growth factor reduced Matrigel

PDGF:

platelet-derived growth factor

RBC:

red blood cell

SMA:

smooth muscle actin

TGFβ:

transforming growth factor beta

VEGF:

vascular endothelial growth factor

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Acknowledgements

The authors thank Steven Simske, PhD for helpful discussion and editing. GFM was provided by Sulzer Biologics, Inc. This work was funded by NIH grant number HL07171.

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Authors and Affiliations

  1. CVP Research Lab, University of Colorado, Health Science Center, Denver, Colorado, USA

    Mark Roedersheimer, James West & Julie Harral

  2. Sulzer Biologics Inc., Wheat Ridge, Colorado, USA

    Mark Roedersheimer & James Benedict

  3. Department of Pathology, University of Colorado, Health Sciences Center, Denver, Colorado, USA

    William Huffer

  4. CVP Research Lab, University of Colorado, Health Science Center, 4200 E. Ninth Avenue, Denver, CO, 80262, USA

    Mark Roedersheimer

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  1. Mark Roedersheimer
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  2. James West
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Correspondence to Mark Roedersheimer.

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Roedersheimer, M., West, J., Huffer, W. et al. A bone-derived mixture of TGFβ-superfamily members forms a more mature vascular network than bFGF or TGF-β2 in vivo . Angiogenesis 8, 327–338 (2006). https://doi.org/10.1007/s10456-005-9022-9

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  • DOI: https://doi.org/10.1007/s10456-005-9022-9

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