Article

PDF
Access to the PDF text
Advertising


Free Article !

Archives of cardiovascular diseases
Volume 102, n° S1
page 36 (mars 2009)
Doi : 10.1016/S1875-2136(09)72212-0
Themes et posters

D002 Sonic hedgehog induces angiogenesis via Rho kinase—dependent MMP-9 and osteopontin expression
 

M.-A. Renault 1, 2, J. Roncalli 2, J. Tongers 2, T. Thorne 2, S. Misener 2, O.-L. Volpert 3, S. Metha 4, A. Burg 4, C. Luedemann 4, G. Qin 2, R. Kishore 2, D.-W. Losordo 2
1 Inserm U828, Bordeaux, France 
2 Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, USA 
3 Department of Urology, Northwestern University, Chicago, USA 
4 st Elizabeth Medical Center, Boston, USA 

@@#100979@@
Rationale and Objectives

The morphogen Sonic Hedgehog (Shh) is known to promote neovascularization in adults via indirect induction of pro-angiogenic cytokine expression by fibroblasts. Direct effects of Shh on endothelial cell (EC) function and angiogenesis, however, have not been characterized. Accordingly, we performed a series of in vitro and in vivo studies to evaluate the direct effects of Shh on EC and to investigate certain mechanisms by which Shh modulates angiogenesis.

Methods and Results

Our data disclose that Shh promotes capillary morphogenesis (tube length on Matrigel™ increased to 271±50 % of the length in untreated cells), induces EC migration (191±35 %) and increases EC expression of matrix metalloproteinase 9 (MMP-9) and osteopontin (OPN), which are shown to be essential for Shh-induced angiogenesis both in vitro and in vivo. Shh effects in ECs, however, occur while Gli-dependent transcription is not modulated. Furthemore, our studies show that changes in gene expression and EC migration are mediated by Shh induction of Rho. The Rho dependence of Shh-induced EC angiogenic activity is documented in vitro using dominant negative constructs for RhoA and Rho kinase (ROCK), showing that RhoA and ROCK blockade attenuates Shh induced migration and tube formation, as well as the Shh induced expression of MMP-9 and OPN. In vivo in the mouse corneal angiogenesis model pharmacologic inhibition of ROCK blocks Shh induced angiogenesis, confirming the ROCK dependence of this process. Furthermore, in MMP-9 and OPN null mice Shh induced angiogenesis also blocked, indicating that Shh induced angiogenesis is also dependent on MMP-9 and OPN expression

Conclusion

These data elucidate an entirely novel, “nonclassical” pathway by which Shh directly modulates EC phenotype and angiogenic activity.

The full text of this article is available in PDF format.
The full text of this article is available in PDF format.
Click here to see it.

Top of the page

© 2009  Elsevier Masson SAS. All Rights Reserved.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline
You can move this window by clicking on the headline
@@#110903@@