HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "insideout" signaling to extracellular matrix by preventing RhoA activation

Hanshi Xu, Lixia Zeng, Hui Peng, Sheldon Chen, Jonathan Jones, Teng Leong Chew, Mehran M. Sadeghi, Yashpal S. Kanwar, Farhad R. Danesh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert modulatory effects on a number of cell signaling cascades by preventing the synthesis of various isoprenoids derived from the mevalonate pathway. In the present study, we describe a novel pleiotropic effect of HMG-CoA reductase inhibitors, also commonly known as statins, on vascular endothelial growth factor (VEGF)-induced type IV collagen accumulation. VEGF is an angiogenic polypeptide that is also known to play a central role in endothelial cell permeability and differentiation. Recently, VEGF has also been implicated in promoting extracellular matrix (ECM) accumulation, although the precise signaling mechanism that mediates VEGF-induced ECM expansion remains poorly characterized. Elucidation of the mechanisms through which VEGF exerts its effect on ECM is clearly a prerequisite for both understanding the complex biology of this molecule as well as targeting VEGF in several pathological processes. To this end, this study explored the underlying molecular mechanisms mediating VEGF-induced ECM expansion in mesangial cells. Our findings show that VEGF stimulation elicits a robust increase in ECM accumulation that involves RhoA activation, an intact actin cytoskeleton, and β1-integrin activation. Our data also indicate that simvastatin, via mevalonate depletion, reverses VEGF-induced ECM accumulation by preventing RhoA activation.

Original languageEnglish (US)
Pages (from-to)F995-F1004
JournalAmerican Journal of Physiology - Renal Physiology
Volume291
Issue number5
DOIs
StatePublished - 2006

Keywords

  • Focal adhesion
  • Integrins
  • Mevalonate

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "insideout" signaling to extracellular matrix by preventing RhoA activation'. Together they form a unique fingerprint.

Cite this