Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells

Marie Ange Renault, Jérôme Roncalli, Jörn Tongers, Tina Thorne, Ekaterina Klyachko, Sol Misener, Olga V. Volpert, Shanu Mehta, Aaron Burg, Corinne Luedemann, Gangjian Qin, Raj Kishore, Douglas W. Losordo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

The morphogen Sonic hedgehog (Shh) promotes neovascularization in adults by inducing pro-angiogenic cytokine expression in fibroblasts; however, the direct effects of Shh on endothelial cell (EC) function during angiogenesis are unknown. Our findings indicate that Shh promotes capillary morphogenesis (tube length on Matrigel™ increased to 271 ± 50% of the length in untreated cells, p=0.00003), induces EC migration (modified Boyden chamber assay, 191 ± 35% of migration in untreated cells, p=0.00009), and increases EC expression of matrix metalloproteinase 9 (MMP-9) and osteopontin (OPN) mRNA (real-time RT-PCR), which are essential for Shh-induced angiogenesis both in vitro and in vivo. Shh activity in ECs is mediated by Rho, rather than through the "classic" Shh signaling pathway, which involves the Gli transcription factors. The Rho dependence of Shh-induced EC angiogenic activity was documented both in vitro, with dominant-negative RhoA and Rho kinase (ROCK) constructs, and in vivo, with the ROCK inhibitor Y27632 in the mouse corneal angiogenesis model. Finally, experiments performed in MMP-9- and OPN-knockout mice confirmed the roles of the ROCK downstream targets MMP-9 and OPN in Shh-induced angiogenesis. Collectively, our results identify a "nonclassical" pathway by which Shh directly modulates EC phenotype and angiogenic activity.

Original languageEnglish (US)
Pages (from-to)490-498
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number3
DOIs
StatePublished - Sep 2010

Keywords

  • Angiogenesis
  • Endothelial cells
  • Gli transcription factors
  • Ischemia
  • Sonic hedgehog

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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