Synergistic Effect of Hemodynamic Environment and Dyslipidemia on Endothelial Biomechanics
thesisposted on 2017-10-31, 00:00 authored by Elizabeth Le Master
The onset and progression of atherosclerosis is due to the combination of several different factors. Plaque development at its nascent stage begins at the endothelial monolayer lining the inner arterial surface. Disturbed flow is well-known to induce endothelial dysfunction and combined with plasma dyslipidemia facilitate atherosclerotic plaque formation. Specifically, it has been shown that atherosclerosis develops in the vascular regions exposed to recirculating disturbed flow patterns and patients with cardiovascular disease have increased plasma levels of pro-atherogenic low density lipoprotein and its oxidized form. Little research, though, has focused on the combined impact of disturbed flow and dyslipidemia on endothelial biomechanical properties. In this dissertation, the overall goal was to determine the impact of disturbed flow on endothelial stiffness and the role of oxidized LDL/dyslipidemia in this process. We provide evidence that oxLDL uptake into endothelial cells is enhanced under disturbed flow, a process that is mediated by oxLDL receptor CD36, but not Lox1, and endocytotic caveolae. Furthermore, this increase in oxLDL uptake resulted in cellular stiffening in vitro and ex vivo measurements show enhanced stiffness in the pro-atherogenic disturbed flow regions of the aortic arch in WT mice, an effect that is abolished in mice globally deficient in CD36 and caveolin1 protein. This observation persisted even when challenged with a high fat diet. In summary, the results provided in this dissertation provide substantial evidence that plasma dyslipidemia results in endothelial stiffening at the pro-atherogenic region of the aortic arch, and demonstrate that this effect is mediated by oxLDL uptake, the oxLDL receptor CD36 and endocytotic caveolae. We propose, therefore, that increased uptake of oxLDL and endothelial stiffening in the athero-prone regions of the aorta are important factors in the local disruption of the endothelial permeability barrier and the onset of the inflammatory response.