Low-density lipoprotein receptor knockout mice exhibit exaggerated microvascular responses to inflammatory stimuli.
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-alpha (TNF-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 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.
Henninger
D D
DD
Department of Physiology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Gerritsen
M E
ME
Granger
D N
DN
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D007962:Leukocytes / Q000166:cytology / Q000502:physiology*; D007975:Leukotriene B4 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000098:blood supply; D010972:Platelet Activating Factor / Q000494:pharmacology; D011973:Receptors, LDL / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D010972:Platelet Activating Factor; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4