Abstract: The uptake and transport of lipids from the lumen to the sub-endothelium is important in vascular and lung diseases. We demonstrated the critical role of caveolin-1 in endothelial uptake of lipids. Cav1-/-/ApoE-/- mice showed decrease in atherosclerotic plaque formation when compared to ApoE-/- mice, whereas EC specific overexpression of Cav-1 in mice leads to increase in lipid accumulation in the vessel wall, indicating endothelial caveolin-1 plays an important role in lipid transport in endothelial cells. As little is known about the role of caveolin-1 in atherosclerosis progression, utilizing EC specific inducible Cav-1 knockout mice we are investigate the role of caveolin-1 at each stage of atherosclerosis. Currently, we are generating Scl.Cre+/+/Cav-1lox/lox/ApoE-/- mice to induce the deletion of EC-Cav-1 in an age-dependent manner in mice to study this question.
We are also investigating modifications to caveolin-1 and the caveolae endocytotic machinery in human ECs following exposure to oxLDL (100 µg/ml). Preliminary data demonstrate that oxLDL-induces an increase in the phosphorylation of Cav-1 (pY14) and eNOS (pS1177), which are integral post-translational modifications in the formation and release of caveolae (Zimnicka et al., 2016). Also, 30 min exposure to oxLDL had no effect on the interaction between β-catenin and VE-cadherin or their expression, which suggests that short-term exposure of ECs to oxLDL and subsequent uptake is independent of AJ disruption.
We also demonstrated that disturbed flow (DF) induces an increase in oxLDL uptake in human ECs. To determine whether physiological blood flow patterns promote post-translational modifications to Cav-1, we exposed human ECs for short (30 min) and long (48 hr) durations. Preliminary studies revealed that when ECs are exposed to 30 min of LF or DF (as compared to static conditions), there was no significant difference in Cav-1 pY14, while eNOS pS1177 increased. When human ECs were exposed to disturbed flow (DF) for 48 hr, we observed a decrease in Cav-1 pY14 and an increase in total caveolin-1 expression level. In these ongoing studies, we are conducting a thorough time course analysis of the effect of DF and laminar flow (LF) on caveolin-1 and its modifications.