Leukocyte-Endothelium Interaction During the Early Stages of Hypercholesterolemia in the Rabbit

Role of P-Selectin, ICAM-1, and VCAM-1

From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Allan M. Lefer, PhD, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799.

Abstract—The early effects of hypercholesterolemia on leukocyte-endothelium interaction were studied in vivo in the rabbit mesenteric microcirculation. Rabbits fed a 0.5% high-cholesterol (HC) diet showed elevated plasma cholesterol levels during the 1 to 2 weeks of HC feeding (P<0.001 versus control diet–fed rabbits). Intravital microscopy of mesenteric venules revealed that leukocyte rolling had increased 10-fold (P<0.001 versus control-fed group) at the end of the first week of the HC diet, which was sustained after 2 weeks of HC feeding (P<0.001 versus control-fed rabbits). Firm adherence of leukocytes to the endothelium was moderately increased after a 1-week period of hypercholesterolemia (P<0.05) but increased by 12-fold at 2 weeks (P<0.001 versus control diet–fed and P<0.01 versus 1-week HC–fed rabbits). Upregulation of the endothelial cell adhesion molecules P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was observed immunohistochemically on the intestinal microvascular endothelium of HC-fed rabbits. P-selectin was maximally expressed within the first week of the HC diet and remained elevated during the second week of cholesterol feeding (P<0.01 versus control). In contrast, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were moderately upregulated at 1 week but were highly expressed after 2 weeks of the HC diet (P<0.05 and P<0.001 versus control, respectively). Basal release of NO from both mesenteric microvascular and aortic endothelium in cholesterol-fed rabbits was progressively reduced after 1 (P<0.05) and 2 (P<0.01) weeks. Our data suggest that enhanced leukocyte-endothelium interaction occurs in vivo in the rabbit microcirculation during the first 2 weeks of hypercholesterolemia. This phenomenon is associated with impaired basal NO release and progressive endothelial surface expression of endothelial cell adhesion molecules (ie, P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) in the microvasculature.

Key Words: intravital microscopy • cell adhesion molecules • nitric oxide • microvascular endothelium

This article has been cited by other articles:

				K. Y. Stokes, S. Gurwara, and D. N. Granger T-Cell-Derived Interferon-{gamma} Contributes to Arteriolar Dysfunction During Acute Hypercholesterolemia Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1998 - 2004. [Abstract] [Full Text] [PDF]

				M.-h. Kim, P. R. Carter, and N. R. Harris P-selectin-mediated adhesion impairs endothelium-dependent arteriolar dilation in hypercholesterolemic mice Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H632 - H638. [Abstract] [Full Text] [PDF]

				D. K. Brake, E. O. Smith, H. Mersmann, C. W. Smith, and R. L. Robker ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1232 - C1239. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Aikawa, P. Alcaide, F. W. Luscinskas, P. Libby, and F. M. Sacks Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells Circulation, August 15, 2006; 114(7): 681 - 687. [Abstract] [Full Text] [PDF]

				T. Miyamoto, H. Yumoto, Y. Takahashi, M. Davey, F. C. Gibson III, and C. A. Genco Pathogen-Accelerated Atherosclerosis Occurs Early after Exposure and Can Be Prevented via Immunization Infect. Immun., February 1, 2006; 74(2): 1376 - 1380. [Abstract] [Full Text] [PDF]

				H.-H. Chou, H. Yumoto, M. Davey, Y. Takahashi, T. Miyamoto, F. C. Gibson III, and C. A. Genco Porphyromonas gingivalis Fimbria-Dependent Activation of Inflammatory Genes in Human Aortic Endothelial Cells Infect. Immun., September 1, 2005; 73(9): 5367 - 5378. [Abstract] [Full Text] [PDF]

				K. Y Stokes and D. N. Granger The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia? J. Physiol., February 1, 2005; 562(3): 647 - 653. [Abstract] [Full Text] [PDF]

				P. J de Kam, A. A Voors, F. Fici, D. J van Veldhuisen, and W. H van Gilst Review: The revised role of ACE-inhibition after myocardial infarction in the thrombolytic/primary PCI era Journal of Renin-Angiotensin-Aldosterone System, December 1, 2004; 5(4): 161 - 168. [Abstract] [PDF]

				A. Tailor, D. J. Lefer, and D. N. Granger HMG-CoA reductase inhibitor attenuates platelet adhesion in intestinal venules of hypercholesterolemic mice Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1402 - H1407. [Abstract] [Full Text] [PDF]

				M. Ishikawa, K. Y. Stokes, J. H. Zhang, A. Nanda, and D. N. Granger Cerebral Microvascular Responses to Hypercholesterolemia: Roles of NADPH Oxidase and P-Selectin Circ. Res., February 6, 2004; 94(2): 239 - 244. [Abstract] [Full Text] [PDF]

				G. Desideri, G. Croce, M. Tucci, G. Passacquale, S. Broccoletti, L. Valeri, A. Santucci, and C. Ferri Effects of Bezafibrate and Simvastatin on Endothelial Activation and Lipid Peroxidation in Hypercholesterolemia: Evidence of Different Vascular Protection by Different Lipid-Lowering Treatments J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5341 - 5347. [Abstract] [Full Text] [PDF]

				A. A. Constantinescu, H. Vink, and J. A.E. Spaan Endothelial Cell Glycocalyx Modulates Immobilization of Leukocytes at the Endothelial Surface Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1541 - 1547. [Abstract] [Full Text] [PDF]

				A. Tailor and D. N. Granger Hypercholesterolemia Promotes P-Selectin-Dependent Platelet-Endothelial Cell Adhesion in Postcapillary Venules Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 675 - 680. [Abstract] [Full Text] [PDF]

				M. Chen, C. Capps, J. T. Willerson, and P. Zoldhelyi E2F-1 Regulates Nuclear Factor-{kappa}B Activity and Cell Adhesion: Potential Antiinflammatory Activity of the Transcription Factor E2F-1 Circulation, November 19, 2002; 106(21): 2707 - 2713. [Abstract] [Full Text] [PDF]

				G. Booth, T. J. Stalker, A. M. Lefer, and R. Scalia Mechanisms of Amelioration of Glucose-Induced Endothelial Dysfunction Following Inhibition of Protein Kinase C In Vivo Diabetes, May 1, 2002; 51(5): 1556 - 1564. [Abstract] [Full Text] [PDF]

				M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]

				T. Suwa, J. C. Hogg, K. B. Quinlan, A. Ohgami, R. Vincent, and S. F. van Eeden Particulate air pollution induces progression of atherosclerosis J. Am. Coll. Cardiol., March 20, 2002; 39(6): 935 - 942. [Abstract] [Full Text] [PDF]

				M. Namiki, S. Kawashima, T. Yamashita, M. Ozaki, T. Hirase, T. Ishida, N. Inoue, K.-i. Hirata, A. Matsukawa, R. Morishita, et al. Local Overexpression of Monocyte Chemoattractant Protein-1 at Vessel Wall Induces Infiltration of Macrophages and Formation of Atherosclerotic Lesion: Synergism With Hypercholesterolemia Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 115 - 120. [Abstract] [Full Text] [PDF]

				C. G. Kevil, R. P. Patel, and D. C. Bullard Essential role of ICAM-1 in mediating monocyte adhesion to aortic endothelial cells Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1442 - C1447. [Abstract] [Full Text] [PDF]

				J. A. Ronald, C. V. Ionescu, K. A. Rogers, and M. Sandig Differential regulation of transendothelial migration of THP-1 cells by ICAM-1/LFA-1 and VCAM-1/VLA-4 J. Leukoc. Biol., October 1, 2001; 70(4): 601 - 609. [Abstract] [Full Text] [PDF]

				N. Methia, P. Andre, C. V. Denis, M. Economopoulos, and D. D. Wagner Localized reduction of atherosclerosis in von Willebrand factor-deficient mice Blood, September 1, 2001; 98(5): 1424 - 1428. [Abstract] [Full Text] [PDF]

				D. Giugliano, F. Nappo, L. Coppola, L. Miguel Blanco-Colio, C. Bustos, M. Ortego, M. Angel Hernandez-Presa, P. Cancelas, J. Gomez-Gerique, J. Egido, et al. Pizza and Vegetables Don't Stick to the Endothelium Response Circulation, August 14, 2001; 104 (7): e34 - e35. [Full Text] [PDF]

				R. Scalia, M. E. Gooszen, S. P. Jones, M. Hoffmeyer, D. M. Rimmer III, S. D. Trocha, P. L. Huang, M. B. Smith, A. M. Lefer, and D. J. Lefer Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E-Deficient Mice Circulation, May 29, 2001; 103(21): 2598 - 2603. [Abstract] [Full Text] [PDF]

				K. Y. Stokes, E. C. Clanton, J. M. Russell, C. R. Ross, and D. N. Granger NAD(P)H Oxidase-Derived Superoxide Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circ. Res., March 16, 2001; 88(5): 499 - 505. [Abstract] [Full Text] [PDF]

				K. K. Koh Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability Cardiovasc Res, September 1, 2000; 47(4): 648 - 657. [Abstract] [Full Text] [PDF]

				T. M. Calderon, S. D. Gertz, I. J. Sarembock, J. A. Berliner, J. T. Fallon, M. B. Taubman, and J. W. Berman Induction of IG9 Monocyte Adhesion Molecule Expression in Smooth Muscle and Endothelial Cells After Balloon Arterial Injury in Cholesterol-Fed Rabbits Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1293 - 1300. [Abstract] [Full Text] [PDF]

				K. J. Williams, R. Scalia, K. D. Mazany, W. V. Rodrigueza, and A. M. Lefer Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1033 - 1039. [Abstract] [Full Text] [PDF]

				C. D. Collard, A. Agah, W. Reenstra, J. Buras, and G. L. Stahl Endothelial Nuclear Factor-{kappa}B Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement : Inhibition With Anti-Human C5 Therapy or cGMP Analogues Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2623 - 2629. [Abstract] [Full Text] [PDF]

				A. M Dart and J. P.F Chin-Dusting Lipids and the endothelium Cardiovasc Res, August 1, 1999; 43(2): 308 - 322. [Abstract] [Full Text] [PDF]

				C. L. Ramos, Y. Huo, U. Jung, S. Ghosh, D. R. Manka, I. J. Sarembock, and K. Ley Direct Demonstration of P-Selectin– and VCAM-1–Dependent Mononuclear Cell Rolling in Early Atherosclerotic Lesions of Apolipoprotein E–Deficient Mice Circ. Res., June 11, 1999; 84(11): 1237 - 1244. [Abstract] [Full Text] [PDF]

				D. J. Lefer and D. N. Granger Monocyte Rolling in Early Atherogenesis : Vital Role in Lesion Development Circ. Res., June 11, 1999; 84(11): 1353 - 1355. [Full Text] [PDF]

				M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]