© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Hypertension and Endothelial Dysfunction in Apolipoprotein E Knockout Mice
From the Departments of Cardiovascular Research (R.Y., L.P.-B., A.K.O., S.B., H.J.), Pathology (N.D.), and Molecular Biology (O.O.), Genentech, Inc, South San Francisco, Calif.
Correspondence to Hongkui Jin, MD, Department of Cardiovascular Research, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080. E-mail hkj{at}gene.com
Abstract—Mice lacking ApoE (Apoe–/–) develop initially hypercholesterolemia and latterly atherosclerosis. This study examined hemodynamics and endothelial function in 6-week-old Apoe–/– mice with hypercholesterolemia only, 7.5-months-old Apoe–/– mice with both hypercholesterolemia and atherosclerosis, and age matched controls. One day after implantation of catheters into the carotid artery, arterial pressure was measured in conscious, unrestrained mice. Compared with the respective controls, there was a significant increase in arterial pressure and the ratio of left ventricular weight to body weight in 7.5-month-old Apoe–/– mice but not in 6-week-old Apoe–/– mice. Histopathological analysis demonstrated significant renal artery disease in the form of extensive atheromatous plaques only in 7.5-month-old Apoe–/– mice, whereas no atherosclerotic lesions were found in 6-week-old Apoe–/– mice. For evaluation of endothelial function, a laser Doppler perfusion imager with a computer-controlled optical scanner was used to measure cutaneous blood perfusion on the dorsal side of one hind paw before and after topical application of mustard oil, which is known to induce nitric oxide–mediated vasodilation. The mustard oil treatment elicited a substantial increase in blood perfusion (P<0.01), which was similar between 6-week-old Apoe–/– mice and controls but significantly blunted in 7.5-month-old Apoe–/– mice versus control mice, suggesting nitric oxide–mediated vasodilation is diminished in 7.5-month-old Apoe–/– mice but not in 6-week-old Apoe–/– mice. In contrast, the increase in blood perfusion induced by topical administration of cilostazol, which induces vasodilation via cyclic adenosine monophosphate, was not different between 7.5-month-old Apoe–/– mice and controls. Thus hypertension and endothelial dysfunction observed in 7.5-month-old Apoe–/– mice may be due mainly to atherosclerosis.
Key Words: hypertension • endothelial dysfunction • Apoe–/– mice • nitric oxide • atherosclerosis
This article has been cited by other articles:
 |
|
 |
|
  I. J. Andersson, Y.-Y. Jiang, and S. T. Davidge Maternal stress and development of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2009; 296(3): R663 - R671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Lloyd, J. McCormick, J. Helmering, K. W. Kim, M. Wang, P. Fordstrom, S. A. Kaufman, R. A. Lindberg, and M. M. Veniant Generation and characterization of two novel mouse models exhibiting the phenotypes of the metabolic syndrome: Apob48-/-Lepob/ob mice devoid of ApoE or Ldlr Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E496 - E505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Isenberg, F. Hyodo, L. K. Pappan, M. Abu-Asab, M. Tsokos, M. C. Krishna, W. A. Frazier, and D. D. Roberts Blocking Thrombospondin-1/CD47 Signaling Alleviates Deleterious Effects of Aging on Tissue Responses to Ischemia Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2582 - 2588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Kuhlencordt, S. Hotten, J. Schodel, S. Rutzel, K. Hu, J. Widder, A. Marx, P. L. Huang, and G. Ertl Atheroprotective Effects of Neuronal Nitric Oxide Synthase in Apolipoprotein E Knockout Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1539 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mineo, H. Deguchi, J. H. Griffin, and P. W. Shaul Endothelial and Antithrombotic Actions of HDL Circ. Res., June 9, 2006; 98(11): 1352 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ponten, E. Bergsten Folestad, K. Pietras, and U. Eriksson Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic Mice Circ. Res., November 11, 2005; 97(10): 1036 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M.P. Arruda, V. A. Peotta, S. S. Meyrelles, and E. C. Vasquez Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension Hypertension, October 1, 2005; 46(4): 932 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Troen, E. Lutgens, D. E. Smith, I. H. Rosenberg, and J. Selhub The atherogenic effect of excess methionine intake PNAS, December 9, 2003; 100(25): 15089 - 15094. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsumoto, L. V. d'uscio, D. Eguchi, M. Akiyama, L. A. Smith, and Z. S. Katusic Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 103 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Alexander, J. W. Knowles, T. Nishikimi, and N. Maeda Increased Atherosclerosis and Smooth Muscle Cell Hypertrophy in Natriuretic Peptide Receptor A-/-Apolipoprotein E-/- Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1077 - 1082. [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]
|
|
|
|
 |
|
 P. W Shaul Endothelial nitric oxide synthase, caveolae and the development of atherosclerosis J. Physiol., February 15, 2003; 547(1): 21 - 33. [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]
|
|
|
|
 |
|
 P. Bruneval, J. Bariety, M.-F. Belair, C. Mandet, D. Heudes, and A. Nicoletti Mesangial expansion associated with glomerular endothelial cell activation and macrophage recruitment is developing in hyperlipidaemic apoE null mice Nephrol. Dial. Transplant., December 1, 2002; 17(12): 2099 - 2107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. MINEO and P.W. SHAUL Modulation of Endothelial NO Production by High-density Lipoprotein Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 459 - 470. [Abstract] [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]
|
|
|
|
|
|
J. Chen, P. J. Kuhlencordt, J. Astern, R. Gyurko, and P. L. Huang Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice Circulation, November 13, 2001; 104(20): 2391 - 2394. [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]
|
|
|
|
|
|
P. J. Kuhlencordt, R. Gyurko, F. Han, M. Scherrer-Crosbie, T. H. Aretz, R. Hajjar, M. H. Picard, and P. L. Huang Accelerated Atherosclerosis, Aortic Aneurysm Formation, and Ischemic Heart Disease in Apolipoprotein E/Endothelial Nitric Oxide Synthase Double-Knockout Mice Circulation, July 24, 2001; 104(4): 448 - 454. [Abstract] [Full Text] [PDF]
|
|