© 1997 American Heart Association, Inc.
Articles |
Low-Density Lipoprotein Receptor Knockout Mice Exhibit Exaggerated Microvascular Responses to Inflammatory Stimuli
From the Department of Physiology (D.D.H., D.N.G.), Louisiana State University Medical Center, Shreveport, and the Institute for Bone and Joint Disease and Cancer (M.E.G.), Bayer Corp, West Haven, Conn.
Correspondence to D. Neil Granger, PhD, Department of Physiology and Biophysics, LSU Medical Center, 1501 E Kings Hwy, Shreveport, LA 71130-3932. E-mail dgrang{at}lsumc.edu
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-
(TNF-). 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-. Plasma TNF- 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.
Key Words: hypercholesterolemia • inflammation • tumor necrosis factor • leukotriene • platelet-activating factor
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