HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation.
The beneficial effects of statins are usually assumed to stem from their ability to reduce cholesterol biosynthesis. However, because statins are potent inhibitors of the mevalonate, which governs diverse cell signaling pathways, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may also result in pleiotropic effects. The present study describes a novel pleiotropic effect of statins on vascular endothelial growth factor (VEGF)-induced glomerular endothelial cell (GEnC) hyperpermeability. Using live cell imaging with green fluorescent protein-tagged myosin regulatory light chain (MLC) and correlative biochemical analyses, we investigated 1) VEGF signaling pathway leading to GEnC hyperpermeability and 2) the modulatory effects of statins on VEGF signaling. Our findings indicate that VEGF stimulation elicits a robust increase in GEnC permeability. The signaling pathway that mediates VEGF-induced GEnC hyperpermeability involves RhoA activation leading to actin cytoskeletal remodeling, MLC diphosphorylation, and enhanced paracellular gap formation. Remarkably, cotreatment of endothelial cells with simvastatin, a hydrophobic statin, reversed VEGF-induced GEnC hyperpermeability by preventing MLC diphosphorylation, and cytoskeletal remodeling. In summary, this study identifies RhoA and MLC phosphorylation as key mediators of VEGF-induced endothelial cell hyperpermeability and demonstrates the modulatory effects of statins on VEGF signaling pathway.
Zeng
Lixia
L
Division of Nephrology/Hypertension, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Xu
Hanshi
H
Chew
Teng-Leong
TL
Eng
Eudora
E
Sadeghi
Mehran M
MM
Adler
Stephen
S
Kanwar
Yashpal S
YS
Danesh
Farhad R
FR
D000199:Actins / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000473:pathology; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000473:pathology; D008798:Mevalonic Acid / Q000494:pharmacology; D018613:Microscopy, Confocal; D008954:Models, Biological; D015233:Models, Statistical; D018994:Myosin Light Chains / Q000737:chemistry* / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018994:Myosin Light Chains; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid