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The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors

Abstract

Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, characterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.

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Figure 1: Ptch expression and activation in postnatal cardiovascular tissues.
Figure 2: Shh increases limb salvage, blood flow and capillary density in the setting of ischemia.
Figure 3: Shh-induced angiogenesis has unusual morphological characteristics.
Figure 4: Shh acts upon stromal cells and induces VEGF production.
Figure 5: Shh upregulates Ptch, VEGF and angiopoietins in human fibroblasts.

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References

  1. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  Google Scholar 

  2. Johnson, R.L. & Tabin, C.J. Molecular models for vertebrate limb development. Cell 90, 979–990 (1997).

    Article  CAS  Google Scholar 

  3. Pepicelli, C.V., Lewis, P.M. & McMahon, A.P. Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr. Biol. 8, 1083–1086 (1998).

    Article  CAS  Google Scholar 

  4. Ramalho-Santos, M., Melton, D.A. & McMahon, A.P. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127, 2763–2772 (2000).

    CAS  PubMed  Google Scholar 

  5. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  Google Scholar 

  6. St-Jacques, B., Hammerschmidt, M. & McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072–2086 (1999).

    Article  CAS  Google Scholar 

  7. Bitgood, M.J., Shen, L. & McMahon, A.P. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr. Biol. 6, 298–304 (1996).

    Article  CAS  Google Scholar 

  8. Parmantier, E. et al. Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths. Neuron 23, 713–724 (1999).

    Article  CAS  Google Scholar 

  9. Porter, J.A., Young, K.E. & Beachy, P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274, 255–259 (1996).

    Article  CAS  Google Scholar 

  10. Pepinsky, R.B. et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J. Biol. Chem. 273, 14037–14045 (1998).

    Article  CAS  Google Scholar 

  11. Fuse, N. et al. Sonic hedgehog signals not as a hydrolytic enzyme but as an apparent ligand for patched. Proc. Natl. Acad. Sci. USA 96, 10992–10999 (1999).

    Article  CAS  Google Scholar 

  12. Zardoya, R., Abouheif, E. & Meyer, A. Evolution and orthology of hedgehog genes. Trends Genet. 12, 496–497 (1996).

    Article  CAS  Google Scholar 

  13. Bitgood, M.J. & McMahon, A.P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell–cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).

    Article  CAS  Google Scholar 

  14. Ingham, P.W. Transducing hedgehog: the story so far. EMBO J. 17, 3505–3511 (1998).

    Article  CAS  Google Scholar 

  15. Stone, D.M. et al. Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J. Cell. Sci. 112, 4437–4448 (1999).

    CAS  PubMed  Google Scholar 

  16. Kogerman, P. et al. Mammalian Suppressor-of-Fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nature Cell. Biol. 1, 312–319 (1999).

    Article  CAS  Google Scholar 

  17. Ding, Q. et al. Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli. Curr. Biol. 9, 1119–1122 (1999).

    Article  CAS  Google Scholar 

  18. Monnier, V., Dussillol, F., Alves, G., Lamour-Isnard, C. & Plessis, A. Suppressor of fused links fused and Cubitus interruptus on the hedgehog signaling pathway. Curr. Biol. 8, 583–586 (1998).

    Article  CAS  Google Scholar 

  19. Sisson, J.C., Ho, K.S., Suyama, K. & Scott, M.P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90, 235–245 (1997).

    Article  CAS  Google Scholar 

  20. Robbins, D.J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesis-related protein costal2. Cell 90, 225–234 (1997).

    Article  CAS  Google Scholar 

  21. Kalderon, D. Hedgehog signalling: Ci complex cuts and clasps. Curr. Biol. 7, R759–R762 (1997).

    Article  CAS  Google Scholar 

  22. Marigo, V., Johnson, R.L., Vortkamp, A. & Tabin, C. Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev. Biol. 180, 273–283 (1996).

    Article  CAS  Google Scholar 

  23. Marigo, V. & Tabin, C. Regulation of patched by sonic hedgehog in the developing neural tube. Proc. Natl. Acad. Sci. USA 93, 9346–9351 (1996).

    Article  CAS  Google Scholar 

  24. Rowitch, D. H. et al. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci. 19, 8954–8965 (1999).

    Article  CAS  Google Scholar 

  25. Brown, L.A. et al. Insights in to early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in type and mutant zebrafish embryos. Mech. Dev. 90, 237–252 (2000).

    Article  CAS  Google Scholar 

  26. Vu, T. H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).

    Article  CAS  Google Scholar 

  27. Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I Proc. Natl. Acad. Sci. USA 97, 4052–4057 (2000).

    Article  CAS  Google Scholar 

  28. Mecklenburg, L. et al. Active hair growth (anagen) is associated with angiogenesis. J. Invest. Dermatol. 114, 909–916 (2000).

    Article  CAS  Google Scholar 

  29. Wang, L.C. et al. Conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration. J. Invest. Dermatol. 114, 901–908 (2000).

    Article  CAS  Google Scholar 

  30. Rivard, A. et al. Age-dependent impairment of angiogenesis. Circulation 99, 111–120 (1999).

    Article  CAS  Google Scholar 

  31. Scheid, A. et al. Hypoxia-regulated gene expression in fetal wound regeneration and adult wound repair. Pediatr. Surg. Int. 16, 232–236 (2000).

    Article  CAS  Google Scholar 

  32. Volpert, O.V., Dameron, K.M. & Bouck, N. Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene 14, 1492–1502 (1997).

    Article  Google Scholar 

  33. Detmar, M. et al. Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptor in human skin. J. Invest. Dermatol. 108, 263–268 (1997).

    Article  CAS  Google Scholar 

  34. Cho, C.S. et al. CD40 engagement on synovial fibroblasts up-regulates production of vascular endothelial growth factor. J. Immunol. 164, 5055–5061 (2000).

    Article  CAS  Google Scholar 

  35. Brogi, E. et al. Indirect angiogenesis cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, while hypoxia upregulates VEGF expression only. Circulation 90, 649–652 (1994).

    Article  CAS  Google Scholar 

  36. Asahara, T. et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ. Res. 83, 233–240 (1998).

    Article  CAS  Google Scholar 

  37. Suri, C. et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 282, 468–471 (1998).

    Article  CAS  Google Scholar 

  38. Tokunaga, T. et al. Vascular endothelial growth factor (VEGF) mRNA isoforms expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br. J. Cancer 77, 998–1002 (1998).

    Article  CAS  Google Scholar 

  39. Gale, N.W. & Yancopoulos, G.D. Growth factors acting via endothelail cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 13, 1055–1066 (1999).

    Article  CAS  Google Scholar 

  40. Holash, J. et al. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 (1999).

    Article  CAS  Google Scholar 

  41. Krishnan, V. et al. Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase. Science 278, 1947–1950 (1997).

    Article  CAS  Google Scholar 

  42. Pereira, F.A. et al. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 13, 1037–1049 (1999).

    Article  CAS  Google Scholar 

  43. Pepinsky, R.B. et al. Mapping sonic hedgehog-receptor interactions by steric interference. J. Biol. Chem. 275, 10995–11001 (2000).

    Article  CAS  Google Scholar 

  44. Couffinhal, T. et al. A mouse model of angiogenesis. Am. J. Pathol. 152, 1667–1679 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Williams, K.P. et al. Functional antagonists of sonic hedgehog reveal the importance of the N terminus for activity. J. Cell. Sci. 112, 4405–4414 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Strauch and E. Garber for the design and generation of recombinant Shh–mIgG1 fusion protein and J. Mead, E. Barban and T. Aprahamian for technical assistance.

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Correspondence to Jeffrey M. Isner.

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Pola, R., Ling, L., Silver, M. et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 7, 706–711 (2001). https://doi.org/10.1038/89083

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