Low-Density Lipoprotein Receptor Knockout Mice Exhibit Exaggerated Microvascular Responses to Inflammatory Stimuli

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Abstract
The objective of this study was to determine whether genetically induced hypercholesterolemia affects leukocyte–endothelial cell interactions in postcapillary venules of the mouse cremaster muscle. Leukocyte adhesion, emigration, and other microvascular parameters were assessed in venules of normal (wild-type) and low-density lipoprotein receptor–deficient (LDLr−/−) mice maintained on either normal rodent chow or on a high cholesterol diet (HCD). Measurements were obtained under control conditions and after administration of either leukotriene B4 (LTB4), platelet-activating factor (PAF), or tumor necrosis factor-α (TNF-α). Elevated numbers of adherent and emigrated leukocytes were observed in venules of LDLr−/− (compared with wild-type) mice on HCD, both under baseline conditions and after exposure to either LTB4, PAF, or TNF-α. Plasma TNF-α levels were also elevated in LDLr−/− versus wild-type mice. Administration of blocking monoclonal antibodies demonstrated that intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, mediates the exaggerated leukocyte–endothelial cell adhesion observed in LDLr−/− mice. The results of these studies indicate that chronic hypercholesterolemia predisposes the microvasculature to intense leukocyte–endothelial cell adhesion in response to different inflammatory stimuli.