LOW-DENSITY-LIPOPROTEIN RECEPTOR KNOCKOUT MICE EXHIBIT EXAGGERATED MICROVASCULAR RESPONSES TO INFLAMMATORY STIMULI

The objective of this study was to determine whether genetically induc ed hypercholesterolemia affects leukocyte- endothelial cell interactio ns in postcapillary venules of the mouse cremaster muscle. Leukocyte a dhesion, 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 contr ol conditions and after administration of either leukotriene B-4 (LTB4 ), platelet-activating factor (PAF), or tumor necrosis factor-alpha (T NF-alpha). 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-alpha. Plasma TNF-alpha levels were also elevated in LDL-/- ve rsus 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-endotheli al cell adhesion observed in LDLr-/- mice. The results of these studie s indicate that chronic hypercholesterolemia predisposes the microvasc ulature to intense leukocyte-endothelial cell adhesion in response to different inflammatory stimuli.