Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2333-2340
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 1997 American Heart Association, Inc.
Articles |
Atherosclerosis, Vascular Remodeling, and Impairment of Endothelium-Dependent Relaxation in Genetically Altered Hyperlipidemic Mice
From the Departments of Internal Medicine and Pharmacology (D.D.H., F.M.F.), Cardiovascular Center, University of Iowa College of Medicine, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081.
Abstract We examined the vascular structure and endothelium-dependent relaxation in two genetic models of hypercholesterolemia: apolipoprotein E (apoE)-knockout mice and combined apoE/LDL receptor–double-knockout mice. Intimal area was increased markedly in proximal segments of thoracic aortas from apoE/LDL receptor–knockout mice [0.13±0.03 (mean±SE) mm2] compared with normal (C57BL/6J) mice (0.002±0.002 mm2, P<.05). Despite intimal thickening, the vascular lumen was not smaller in the aortas of apoE/LDL receptor–knockout mice (0.52±0.03 mm2) than in normal mice (0.50±0.03 mm2). In apoE-deficient mice, intimal thickening was minimal or absent, even though the concentration of plasma cholesterol was only modestly less than that in the double-knockout mouse (14.9±1.1 vs 18.0±1.2 mmol/L, respectively, P<.05). Relaxation of the aorta was examined in vitro in vascular rings precontracted with U46619. In normal mice, acetylcholine produced relaxation, which was markedly attenuated by the nitric oxide synthase inhibitor NG-nitro-L-arginine (100 µM). Relaxation to acetylcholine and the calcium ionophore A23187 was normal in apoE-deficient mice (in which lesions were minimal) but greatly impaired in the proximal segments of thoracic aortas of apoE/LDL receptor–deficient mice, which contained atherosclerotic lesions. Vasorelaxation to nitroprusside was similar in normal and apoE-knockout mice, with modest but statistically significant impairment in atherosclerotic segments of apoE/LDL receptor–knockout mice. In distal segments of the thoracic aorta of apoE/LDL receptor–deficient mice, atherosclerotic lesions were minimal or absent, and the endothelium-dependent relaxation to acetylcholine and calcium ionophore was normal. Thus, in apoE/LDL receptor–knockout mice (a genetic model of hyperlipidemia), there is vascular remodeling with preservation of the aortic lumen despite marked intimal thickening, with impairment of endothelium-dependent relaxation to receptor- and nonreceptor-mediated agonists. Atherosclerosis may be accelerated in the apoE/LDL receptor–double-knockout mouse compared with the apoE-knockout strain alone. We speculate that other factors, such as the absence of LDL receptors, may contribute to the differences in the extent of atherosclerosis in these two models of hyperlipidemia.
Key Words: gene knockout • aorta • atherosclerosis • acetylcholine • hypercholesterolemia
This article has been cited by other articles:
 |
|
 |
|
  D. W. Nuno, V. P. Korovkina, S. K. England, and K. G. Lamping RhoA Activation Contributes to Sex Differences in Vascular Contractions Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1934 - 1940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Stapleton, Adam. G. Goodwill, M. E. James, and J. C. Frisbee Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1110 - R1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Korshunov, S. M. Schwartz, and B. C. Berk Vascular Remodeling: Hemodynamic and Biochemical Mechanisms Underlying Glagov's Phenomenon Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1722 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kitayama, F. M. Faraci, S. R. Lentz, and D. D. Heistad Cerebral Vascular Dysfunction During Hypercholesterolemia Stroke, July 1, 2007; 38(7): 2136 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rahmani, R. P. Cruz, D. J. Granville, and B. M. McManus Allograft Vasculopathy Versus Atherosclerosis Circ. Res., October 13, 2006; 99(8): 801 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ohashi, M. S. Runge, F. M. Faraci, and D. D. Heistad MnSOD Deficiency Increases Endothelial Dysfunction in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2331 - 2336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lorkowska, M. Bartus, M. Franczyk, R. B. Kostogrys, J. Jawien, P. M. Pisulewski, and S. Chlopicki Hypercholesterolemia Does Not Alter Endothelial Function in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1019 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gigante, G. Morlino, M. T. Gentile, M. G. Persico, and S. De Falco Plgf-/-eNos-/- mice show defective angiogenesis associated with increased oxidative stress in response to tissue ischemia FASEB J, May 1, 2006; 20(7): 970 - 972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kyselovic, P. Martinka, Z. Batova, A. Gazova, and T. Godfraind Calcium Channel Blocker Inhibits Western-Type Diet-Evoked Atherosclerosis Development in ApoE-Deficient Mice J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 320 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Lamping, J. Wess, Y. Cui, D. W. Nuno, and F. M. Faraci Muscarinic (M) Receptors in Coronary Circulation: Gene-Targeted Mice Define the Role of M2 and M3 Receptors in Response to Acetylcholine Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1253 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Frank, S. E. Woodman, D. S. Park, and M. P. Lisanti Caveolin, Caveolae, and Endothelial Cell Function Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1161 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Crauwels, C. E. Van Hove, P. Holvoet, A. G. Herman, and H. Bult Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI Cardiovasc Res, July 1, 2003; 59(1): 189 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo Circulation, May 20, 2003; 107(19): 2480 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. de Nigris, L. O. Lerman, S. W. Ignarro, G. Sica, A. Lerman, W. Palinski, L. J. Ignarro, and C. Napoli From the Cover: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress PNAS, February 4, 2003; 100(3): 1420 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gervais, S. Pons, A. Nicoletti, C. Cosson, J.-F. Giudicelli, and C. Richer Fluvastatin Prevents Renal Dysfunction and Vascular NO Deficit in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 183 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Bentzon, G. Pasterkamp, and E. Falk Expansive Remodeling Is a Response of the Plaque-Related Vessel Wall in Aortic Roots of ApoE-Deficient Mice: An Experiment of Nature Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 257 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, M. J. Ryan, L. A. Didion, P. E. Fegan, C. D. Sigmund, and F. M. Faraci Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice Circ. Res., November 15, 2002; 91(10): 938 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Didion, M. J. Ryan, G. L. Baumbach, C. D. Sigmund, and F. M. Faraci Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1569 - H1576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chu, D. D. Heistad, K. L. Knudtson, K. G. Lamping, and F. M. Faraci Quantification of mRNA for Endothelial NO Synthase in Mouse Blood Vessels by Real-Time Polymerase Chain Reaction Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 611 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V d'Uscio, M. Barton, S. Shaw, and T. F Luscher Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice Cardiovasc Res, February 1, 2002; 53(2): 487 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ryan, S. P. Didion, D. R. Davis, F. M. Faraci, and C. D. Sigmund Endothelial Dysfunction and Blood Pressure Variability in Selected Inbred Mouse Strains Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 42 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Godecke, M. Ziegler, Z. Ding, and J. Schrader Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms Cardiovasc Res, January 1, 2002; 53(1): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, L. A. Smith, and Z. S. Katusic Hypercholesterolemia Impairs Endothelium-Dependent Relaxations in Common Carotid Arteries of Apolipoprotein E-Deficient Mice Stroke, November 1, 2001; 32(11): 2658 - 2664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lutgens, E. D. de Muinck, S. Heeneman, and M. J.A.P. Daemen Compensatory Enlargement and Stenosis Develop in ApoE-/- and ApoE*3-Leiden Transgenic Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1359 - 1365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, T. A. Baker, C. B. Mantilla, L. Smith, D. Weiler, G. C. Sieck, and Z. S. Katusic Mechanism of Endothelial Dysfunction in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1017 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Darblade, D. Caillaud, M. Poirot, M.-J. Fouque, J.-C. Thiers, J. Rami, F. Bayard, and J.-F. Arnal Alteration of plasmalemmal caveolae mimics endothelial dysfunction observed in atheromatous rabbit aorta Cardiovasc Res, June 1, 2001; 50(3): 566 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Hartley, A. K. Reddy, S. Madala, B. Martin-McNulty, R. Vergona, M. E. Sullivan, M. Halks-Miller, G. E. Taffet, L. H. Michael, M. L. Entman, et al. Hemodynamic changes in apolipoprotein E-knockout mice Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2326 - H2334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Lamping, D. W. Nuno, E. G. Shesely, N. Maeda, and F. M. Faraci Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1906 - H1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Lentz, R. A. Erger, S. Dayal, N. Maeda, M. R. Malinow, D. D. Heistad, and F. M. Faraci Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta -synthase-deficient mice Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H970 - H975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Liuba, P. Karnani, E. Pesonen, I. Paakkari, A. Forslid, L. Johansson, K. Persson, T. Wadstrom, and R. Laurini Endothelial Dysfunction After Repeated Chlamydia pneumoniae Infection in Apolipoprotein E-Knockout Mice Circulation, August 29, 2000; 102(9): 1039 - 1044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kauser, V. da Cunha, R. Fitch, C. Mallari, and G. M. Rubanyi Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1679 - H1685. [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]
|
|
|
|
|
|
S. Hamasaki, S. T. Higano, J. A. Suwaidi, R. A. Nishimura, K. Miyauchi, D. R. Holmes Jr, and A. Lerman Cholesterol-Lowering Treatment Is Associated With Improvement in Coronary Vascular Remodeling and Endothelial Function in Patients With Normal or Mildly Diseased Coronary Arteries Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 737 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, C. D. Sigmund, F. M. Faraci, and Z. S. Katusic Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen • Editorial Comment Stroke, March 1, 2000; 31(3): 760 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Faraci and C. D. Sigmund Vascular Biology in Genetically Altered Mice : Smaller Vessels, Bigger Insight Circ. Res., December 3, 1999; 85(12): 1214 - 1225. [Full Text] [PDF]
|
|
|
|
|
|
R. Yang, L. Powell-Braxton, A. K. Ogaoawara, N. Dybdal, S. Bunting, O. Ohneda, and H. Jin Hypertension and Endothelial Dysfunction in Apolipoprotein E Knockout Mice Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2762 - 2768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gunnett, D. J. Berg, F. M. Faraci, and G. Feuerstein Vascular Effects of Lipopolysaccharide Are Enhanced in Interleukin-10-Deficient Mice • Editorial Comment Stroke, October 1, 1999; 30(10): 2191 - 2196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. de las Heras, P. Aragoncillo, R. Maeso, S. Vazquez-Perez, J. Navarro-Cid, M. DeGasparo, J. Mann, L. M. Ruilope, V. Cachofeiro, and V. Lahera AT1 Receptor Antagonism Reduces Endothelial Dysfunction and Intimal Thickening in Atherosclerotic Rabbits Hypertension, October 1, 1999; 34(4): 969 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Deckert, G. Lizard, N. Duverger, A. Athias, V. Palleau, F. Emmanuel, M. Moisant, P. Gambert, C. Lallemant, and L. Lagrost Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice : Toward Normalization By Human ApoA-I Expression Circulation, September 14, 1999; 100(11): 1230 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Caligiuri, B. Levy, J. Pernow, P. Thoren, and G. K. Hansson Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice PNAS, June 8, 1999; 96(12): 6920 - 6924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Lamping, D. W. Nuno, D. A. Chappell, and F. M. Faraci Agonist-specific impairment of coronary vascular function in genetically altered, hyperlipidemic mice Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1999; 276(4): R1023 - R1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barton, C. C. Haudenschild, L. V. d'Uscio, S. Shaw, K. Munter, and T. F. Luscher Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice PNAS, November 24, 1998; 95(24): 14367 - 14372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gunnett, Y. Chu, D. D. Heistad, A. Loihl, and F. M. Faraci Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H416 - H421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Carmeliet, L. Moons, and D. Collen Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis Cardiovasc Res, July 1, 1998; 39(1): 8 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Faraci, C. D. Sigmund, E. G. Shesely, N. Maeda, and D. D. Heistad Responses of carotid artery in mice deficient in expression of the gene for endothelial NO synthase Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H564 - H570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dayal, T. Bottiglieri, E. Arning, N. Maeda, M. R. Malinow, C. D. Sigmund, D. D. Heistad, F. M. Faraci, and S. R. Lentz Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine {beta}-Synthase-Deficient Mice Circ. Res., June 8, 2001; 88(11): 1203 - 1209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chu, D. D. Heistad, K. L. Knudtson, K. G. Lamping, and F. M. Faraci Quantification of mRNA for Endothelial NO Synthase in Mouse Blood Vessels by Real-Time Polymerase Chain Reaction Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 611 - 616. [Abstract] [Full Text] [PDF]
|
|