(116ap) Contrasting Effects of Fluvastatin and Simvastatin on Endothelial Invasion

Endothelial invasion is a crucial step in angiogenic blood vessel formation and has ramifications in wound healing, tumor growth, and may have implications in heart disease. During invasion quiescent endothelial cells (ECs) proteolyze their basement membrane, proliferate, and sprout into the extracellular matrix. This process is partially mediated by the extracellular matrix-degrading enzymes matrix metalloproteinases (MMPs) and stimulated by angiogenic growth factors Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (bFGF), as well as the lysosphingolipid Sphingosine-1-Phosphate (S1P). Invasion is distinguishable by dramatic EC morphological changes from simple squamous cells to sprouting structures that ultimately form new lumen.

Cholesterol synthesis is inhibited by a class of drugs called HMG-CoA Reductase inhibitors, also known as statins. Statins are the first line of pharmacological treatment for reducing cholesterol levels when diet and lifestyle changes are not sufficient. 3-hydroxy-3-methylglutaryl-CoenzymeA (HMG-CoA) Reductase is the key rate-determining enzyme of the Mevalonate pathway, the biological process by which dimethylallyl pyrophosphate and isopentyl pyrophosphate (sterol precursors) are synthesized. Statins are effective in reducing the risk of atherosclerosis, a major cause of cardiovascular disease and studies have shown that statins may have secondary protective effects.

In our study, we tested the effects of statins on endothelial cell sprouting response. To investigate whether statins improve endothelial function, we studied the effects of two different statins on regulating endothelial invasion of three-dimensional collagen matrices. The natural product-derived Simvastatin (ZOCOR®) stimulated endothelial invasion whereas the synthetic Fluvastatin (LESCOL®) inhibited invasion. Both were tested at concentrations observed in human plasma and in physiologically relevant conditions. Experiments were designed to test effects from 72-hr pretreatment along with immediate exposure in the assays in the presence of moderate and high levels of S1P. Gelatin zymography performed on conditioned media samples indicated that stimulation and inhibition of invasion did not correspond with differences in MMP activation.