Subendothelial Calcification Increases Surface Roughness and Promotes Lipid Deposition into the Arterial Wall
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Objective
We have previously demonstrated that subendothelial calcification accelerates atherosclerosis in mice. This study addresses a mechanism by which subendothelial calcifications can increase low-density lipoprotein (LDL) uptake into the arterial wall.
Methods
Mice overexpressing tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells (eTNAP mice) were used as a model of calcification. Calcification and atherosclerosis were detected by micro-computed tomography (micro-CT) and histology. The endothelial roughness was characterized by surface metrology. A fluid-structure interaction model was used to calculate wall shear stress (WSS). The uptake of fluorescent LDL was traced in vitro and in vivo . Human arteries were assessed for the prevalence of internal elastic lamina (IEL) calcification.
Results
eTNAP mice developed more severe aortic atherosclerosis than controls on the LDL receptor mutant background (p<0.01). Subendothelial calcifications in eTNAP mice were confirmed by micro-CT. An increase in aortic surface area roughness, including the height, volume, and steepness parameters, was observed in eTNAP mice compared to controls (p<0.01). Calcifications affected near-wall hemodynamics, creating pockets of reduced WSS. Endothelial cells cultured on rough surfaces showed increased LDL uptake compared to cells cultured on smooth collagen (p<0.0001). Fluorescent LDLs were traced to subendothelial calcifications in eTNAP mice but not in controls. In humans, IEL calcification was prevalent in older adults and inversely correlated with arterial diameter (p<0.05).
Conclusion
Subendothelial calcification is sufficient to perturb near-wall hemodynamics, creating localized areas of reduced WSS, consistent with increased LDL uptake near calcified lesions. Subendothelial calcification may represent an alternative or concurrent mechanism for the initiation of atherosclerosis.
Research perspective
What is new?
-
We tested a novel hypothesis that subendothelial microcalcification can initiate atherosclerosis.
-
The study demonstrated that micron-sized subendothelial calcifications, induced by the overexpression of tissue-nonspecific alkaline phosphatase in the endothelium, are sufficient to perturb local hemodynamics, creating pockets of low wall shear stress, consistent with an increase in low-density lipoprotein uptake and deposition into the arterial wall in juxtaposition to calcified lesions.
What are the clinical implications?
-
We suggest that calcification of internal elastic lamina of medium-sized arteries may represent early lesions initiating atherosclerosis; however, the epidemiologic evidence for this theory is currently unavailable.
