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Endothelial Transcytosis of Lipoproteins in Atherosclerosis
Xinbo Zhang1, William C Sessa2, Carlos Fernández-Hernando1
1Vascular Biology and Therapeutics Program, Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, United States.
Insights
Low-density lipoprotein (LDL) transport across the endothelium is crucial for atherosclerosis development. Understanding the molecular mechanisms of LDL transcytosis can lead to new therapies for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Lipid Metabolism
Background:
- Atherosclerosis is initiated by cholesterol accumulation in arteries, with elevated low-density lipoprotein cholesterol (LDL-C) as a major risk factor.
- LDL infiltration and modification within the arterial wall trigger endothelial cell activation and vascular inflammation.
- The precise molecular mechanisms governing LDL transport across the endothelium remain incompletely understood.
Purpose of the Study:
- To review the role of the endothelial cell barrier in regulating lipoprotein transport.
- To summarize current knowledge on the molecular mechanisms of LDL and high-density lipoprotein (HDL) transcytosis across endothelial cells.
- To highlight the relevance of these processes in atherosclerosis progression.
Main Methods:
- Literature review of seminal and recent studies on lipoprotein transport and atherosclerosis.
- Synthesis of findings regarding the molecular players involved in LDL and HDL transcytosis.
- Analysis of the endothelial cell barrier's function in regulating lipoprotein movement.
Main Results:
- LDL transcytosis across endothelium involves caveolae, scavenger receptor B1 (SR-B1), activin receptor-like kinase 1 (ALK1), and LDL receptor (LDLR).
- HDL and apolipoprotein AI transcytosis utilize SR-B1, ATP-Binding cassette transporter A1 (ABCA1), and ABCG1.
- Endothelial cell barrier function critically influences lipoprotein transport and atherosclerosis progression.
Conclusions:
- Understanding lipoprotein transcytosis mechanisms is key to targeting early atherosclerotic events.
- Elucidating these pathways offers potential therapeutic strategies for atherosclerotic vascular disease.
- Further research into endothelial lipoprotein transport can advance cardiovascular disease treatment.
Abstract:
Seminal studies from Nikolai Anichckov identified the accumulation of cholesterol in the arteries as the initial event that lead to the formation of atherosclerotic plaques. Further studies by Gofman and colleagues demonstrated that high levels of circulating low-density lipoprotein cholesterol (LDL-C) was responsible for the accelerated atherosclerosis observed in humans. These findings were confirmed by numerous epidemiological studies which identified elevated LDL-C levels as a major risk factor for cardiovascular disease. LDL infiltrates in the arterial wall and interacts with the proteoglycan matrix promoting the retention and modification of LDL to a toxic form, which results in endothelial cell (EC) activation and vascular inflammation. Despite the relevance of LDL transport across the endothelium during atherogenesis, the molecular mechanism that control this process is still not fully understood. A number of studies have recently demonstrated that low density lipoprotein (LDL) transcytosis across the endothelium is dependent on the function of caveolae, scavenger receptor B1 (SR-B1), activin receptor-like kinase 1 (ALK1), and LDL receptor (LDLR), whereas high-density lipoproteins (HDL) and its major protein component apolipoprotein AI transcytose ECs through SR-B1, ATP-Binding cassette transporter A1 (ABCA1) and ABCG1. In this review article, we briefly summarize the function of the EC barrier in regulating lipoprotein transport, and its relevance during the progression of atherosclerosis. A better understanding of the mechanisms that mediate lipoprotein transcytosis across ECs will help to develop therapies targeting the early events of atherosclerosis and thus exert potential benefits for treating atherosclerotic vascular disease.
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