Genetic Evidence Supporting a Critical Role of Endothelial Caveolin-1 During the Progression of Atherosclerosis

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2009 Jul 9

PMID 19583953

Citations 108

Authors

Carlos Fernandez-Hernando

Jun Yu

Yajaira Suarez

Christoph Rahner

Alberto Davalos

Miguel A Lasuncion

William C Sessa

Affiliations

Soon will be listed here.

Abstract

The accumulation of LDL-derived cholesterol in the artery wall is the initiating event that causes atherosclerosis. However, the mechanisms that lead to the initiation of atherosclerosis are still poorly understood. Here, by using endothelial cell-specific transgenesis of the caveolin-1 (Cav-1) gene in mice, we show the critical role of Cav-1 in promoting atherogenesis. Mice were generated lacking Cav-1 and apoE but expressing endothelial-specific Cav-1 in the double knockout background. Genetic ablation of Cav-1 on an apoE knockout background inhibits the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promotes lesion expansion. Mechanistically, the loss of Cav-1 reduces LDL infiltration into the artery wall, promotes nitric oxide production, and reduces the expression of leukocyte adhesion molecules, effects completely reversed in transgenic mice. In summary, this unique model provides physiological evidence supporting the important role of endothelial Cav-1 expression in regulating the entry of LDL into the vessel wall and the initiation of atherosclerosis.

Citing Articles

Deficiency of Caveolin-1 Aggravates Cardiac Infarction Injury by Disturbing the Endothelial Homeostasis.

Liu C, Zhang J, Qi B, Li Z, Li Q, Wang L Int J Med Sci. 2025; 22(4):920-932.

PMID: 39991756 PMC: 11843147. DOI: 10.7150/ijms.101074.

Inflammation in atherosclerosis: a Big Idea that has underperformed so far.

Williams K Curr Opin Lipidol. 2025; .

PMID: 39846349 PMC: 11888836. DOI: 10.1097/MOL.0000000000000973.

Apolipoprotein B-containing lipoproteins in atherogenesis.

Boren J, Packard C, Binder C Nat Rev Cardiol. 2025; .

PMID: 39743565 DOI: 10.1038/s41569-024-01111-0.

Cardiovascular Risk in Patients with Inflammatory Bowel Diseases-The Role of Endothelial Dysfunction.

Livzan M, Bikbavova G, Lisyutenko N, Romanyuk A, Drapkina O Diagnostics (Basel). 2024; 14(16).

PMID: 39202210 PMC: 11353271. DOI: 10.3390/diagnostics14161722.

Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice.

Lee S, Schleer H, Park H, Jang E, Boyer M, Tao B Nat Cardiovasc Res. 2024; 2(5):438-448.

PMID: 39196046 PMC: 11358031. DOI: 10.1038/s44161-023-00266-2.

References

Hassan G, Williams T, Frank P, Lisanti M . Caveolin-1-deficient aortic smooth muscle cells show cell autonomous abnormalities in proliferation, migration, and endothelin-based signal transduction. Am J Physiol Heart Circ Physiol. 2006; 290(6):H2393-401. DOI: 10.1152/ajpheart.01161.2005. View

Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B . Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science. 2001; 293(5539):2449-52. DOI: 10.1126/science.1062688. View

Fraser R, Dobbs B, Rogers G . Lipoproteins and the liver sieve: the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology. 1995; 21(3):863-74. View

Le Couteur D, Cogger V, McCuskey R, de Cabo R, Smedsrod B, Sorensen K . Age-related changes in the liver sinusoidal endothelium: a mechanism for dyslipidemia. Ann N Y Acad Sci. 2007; 1114:79-87. DOI: 10.1196/annals.1396.003. View

Busse R, Fleming I . Endothelial dysfunction in atherosclerosis. J Vasc Res. 1996; 33(3):181-94. DOI: 10.1159/000159147. View

Galkina E, Ley K . Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007; 27(11):2292-301. DOI: 10.1161/ATVBAHA.107.149179. View

Frank P, Pavlides S, Cheung M, Daumer K, Lisanti M . Role of caveolin-1 in the regulation of lipoprotein metabolism. Am J Physiol Cell Physiol. 2008; 295(1):C242-8. PMC: 2493562. DOI: 10.1152/ajpcell.00185.2008. View

Frank P, Lee H, Park D, Tandon N, Scherer P, Lisanti M . Genetic ablation of caveolin-1 confers protection against atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 24(1):98-105. DOI: 10.1161/01.ATV.0000101182.89118.E5. View

Peterson T, Guicciardi M, Gulati R, Kleppe L, Mueske C, Mookadam M . Caveolin-1 can regulate vascular smooth muscle cell fate by switching platelet-derived growth factor signaling from a proliferative to an apoptotic pathway. Arterioscler Thromb Vasc Biol. 2003; 23(9):1521-7. DOI: 10.1161/01.ATV.0000081743.35125.05. View

10.

Frank P, Lisanti M . Caveolin-1 and caveolae in atherosclerosis: differential roles in fatty streak formation and neointimal hyperplasia. Curr Opin Lipidol. 2004; 15(5):523-9. DOI: 10.1097/00041433-200410000-00005. View

11.

Hilmer S, Cogger V, Fraser R, McLean A, Sullivan D, Le Couteur D . Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat. Hepatology. 2005; 42(6):1349-54. DOI: 10.1002/hep.20937. View

12.

Garcia-Cardena G, Fan R, Stern D, Liu J, Sessa W . Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem. 1996; 271(44):27237-40. DOI: 10.1074/jbc.271.44.27237. View

13.

Liu P, Rudick M, Anderson R . Multiple functions of caveolin-1. J Biol Chem. 2002; 277(44):41295-8. DOI: 10.1074/jbc.R200020200. View

14.

Yu J, Bergaya S, Murata T, Alp I, Bauer M, Lin M . Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J Clin Invest. 2006; 116(5):1284-91. PMC: 1451207. DOI: 10.1172/JCI27100. View

15.

Otway S, Robinson D . The use of a non-ionic detergent (Triton WR 1339) to determine rates of triglyceride entry into the circulation of the rat under different physiological conditions. J Physiol. 1967; 190(2):321-32. PMC: 1365296. DOI: 10.1113/jphysiol.1967.sp008211. View

16.

Razani B, Combs T, Wang X, Frank P, Park D, Russell R . Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem. 2001; 277(10):8635-47. DOI: 10.1074/jbc.M110970200. View

17.

Hassan G, Jasmin J, Schubert W, Frank P, Lisanti M . Caveolin-1 deficiency stimulates neointima formation during vascular injury. Biochemistry. 2004; 43(26):8312-21. DOI: 10.1021/bi049609t. View

18.

Li J, Scherl A, Medina F, Frank P, Kitsis R, Tanowitz H . Impaired phagocytosis in caveolin-1 deficient macrophages. Cell Cycle. 2005; 4(11):1599-607. DOI: 10.4161/cc.4.11.2117. View

19.

Frank P, Cheung M, Pavlides S, Llaverias G, Park D, Lisanti M . Caveolin-1 and regulation of cellular cholesterol homeostasis. Am J Physiol Heart Circ Physiol. 2006; 291(2):H677-86. DOI: 10.1152/ajpheart.01092.2005. View

20.

Kuhlencordt P, Gyurko R, Han F, Scherrer-Crosbie M, Aretz T, Hajjar R . Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation. 2001; 104(4):448-54. DOI: 10.1161/hc2901.091399. View