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Fibroblast growth factor 9 delivery during angiogenesis produces durable, vasoresponsive microvessels wrapped by smooth muscle cells

Nature Biotechnology volume 29, pages 421–427 (2011)Cite this article

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Abstract

The therapeutic potential of angiogenic growth factors has not been realized. This may be because formation of endothelial sprouts is not followed by their muscularization into vasoreactive arteries. Using microarray expression analysis, we discovered that fibroblast growth factor 9 (FGF9) was highly upregulated as human vascular smooth muscle cells (SMCs) assemble into layered cords. FGF9 was not angiogenic when mixed with tissue implants or delivered to the ischemic mouse hind limb, but instead orchestrated wrapping of SMCs around neovessels. SMC wrapping in implants was driven by sonic hedgehog–mediated upregulation of PDGFRβ. Computed tomography microangiography and intravital microscopy revealed that microvessels formed in the presence of FGF9 had enhanced capacity to receive flow and were vasoreactive. Moreover, the vessels persisted beyond 1 year, remodeling into multilayered arteries paired with peripheral nerves. This mature physiological competency was attained by targeting mesenchymal cells rather than endothelial cells, a finding that could inform strategies for therapeutic angiogenesis and tissue engineering.

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Figure 1: FGF9 is not angiogenic but stimulates recruitment of mural cells, including SMCs, to nascent microvessels.
Figure 2: FGF9 drives neovascular maturation by PDGFRβ and SHH signaling.
Figure 3: FGF9 promotes the development of perfusion-competent and vasoreactive microvessels.
Figure 4: FGF9 promotes the development of durable, multilayered microvessels.
Figure 5: FGF9 promotes neovessel maturation and functional recovery following hind limb ischemia.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (FRN-11715), Heart and Stroke Foundation of Ontario (T7081) and Lawson Health Research Institute. J.G.P. holds the Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair, M.D. holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario and R.G. is supported by a New Investigator Award from the Heart and Stroke Foundation of Canada.

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Authors and Affiliations

  1. Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada and London Health Sciences Centre, London, Canada

    Matthew J Frontini, Zengxuan Nong, Robert Gros, Maria Drangova, Caroline O'Neil, Mona N Rahman, Oula Akawi, Hao Yin & J Geoffrey Pickering

  2. Department of Medicine (Cardiology), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada

    J Geoffrey Pickering

  3. Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada

    Matthew J Frontini & J Geoffrey Pickering

  4. Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada

    Maria Drangova, Christopher G Ellis & J Geoffrey Pickering

  5. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada

    Robert Gros

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Contributions

M.J.F. undertook experimentation and contributed to the manuscript preparation. Z.N. performed animal surgeries and tissue immunohistochemistry. R.G. contributed to the intravital microscopy experiments and laser Doppler perfusion studies and undertook gait analyses. M.D. undertook micro-CT angiography and its analysis. C.O. and M.N.R. performed the microarray experiments and cell proliferation and migration studies and C.O. also contributed to the laser Doppler flow analyses. O.A. contributed to the telomere analyses. H.Y. undertook the FGFR activation studies and contributed to manuscript preparation. C.G.E. provided technical support and conceptual advice for intravital experiments. J.G.P. conceived and designed the study and prepared the manuscript.

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Correspondence to J Geoffrey Pickering.

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Competing interests

J.G.P., M.J.F. and Z.N. hold a patent relating to the use of FGF9 in the context of the findings in this report.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 4216 kb)

Supplementary Video 1

Vasomotion of control neovessel (MOV 3379 kb)

Supplementary Video 2

Vasomotion of FGF9-modified neovessel (MOV 3225 kb)

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Frontini, M., Nong, Z., Gros, R. et al. Fibroblast growth factor 9 delivery during angiogenesis produces durable, vasoresponsive microvessels wrapped by smooth muscle cells. Nat Biotechnol 29, 421–427 (2011). https://doi.org/10.1038/nbt.1845

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