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The role of the lymphatic system in cholesterol transport.

Huang LH, Elvington A, Randolph GJ - Front Pharmacol (2015)

Bottom Line: Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream.There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels.New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO, USA.

ABSTRACT
Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

No MeSH data available.


Related in: MedlinePlus

Lymphatic dependent reverse cholesterol transport within the atherosclerotic plaque. In the context of the atherosclerotic plaque environment, removal of plaque cholesterol may be impaired by oxidation and modification of ApoA1 that prevents its ability to accept cholesterol from foam cells to form HDL. Movement of the HDL-cholesterol out of plaques occurs in the direction of interstitial fluid flow with removal likely occurring in adventitial lymphatic vessels.
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Figure 3: Lymphatic dependent reverse cholesterol transport within the atherosclerotic plaque. In the context of the atherosclerotic plaque environment, removal of plaque cholesterol may be impaired by oxidation and modification of ApoA1 that prevents its ability to accept cholesterol from foam cells to form HDL. Movement of the HDL-cholesterol out of plaques occurs in the direction of interstitial fluid flow with removal likely occurring in adventitial lymphatic vessels.

Mentions: The influx, oxidization, and retention of ApoB-containing lipoproteins within the subendothelial space is a key aspect of the initiation of atherosclerosis (Tabas et al., 2007). Recruitment of monocytes, and differentiation into foamy macrophages, drive disease progression (Gautier et al., 2009). As macrophages phagocytize oxidized ApoB-containing lipoproteins, a fatty streak is formed within the intimal layer of the vessel, serving as a marker for the early stage of disease. Foam cells are thought to be inflammatory and necrosis of macrophages alongside invading smooth muscle cells with altered differentiation (Shankman et al., 2015) result in the formation of necrotic core and cholesterol crystals (Glass and Witztum, 2001). Is there a role for lymphatic vessels in plaque progression? A relationship between atherosclerosis and reduced lymphatic transport of cholesterol was hypothesized in the early 1980s (Lemole, 1981; Miller et al., 1992). Lymphatic vessels were later identified within the arterial wall (Johnson, 1969; Nakano et al., 2005; Drozdz et al., 2012). In human diseased vessels, a positive correlation exists between intimal thickness and adventitial lymphatic density (Drozdz et al., 2008), as well as lymphatic dysfunction and atherogenesis (Eliska et al., 2006). Perhaps these results can be interpreted as evidence that lymphatics remodel to facilitate RCT from the intimal environment. It remains unclear and imperfectly studied as to how HDL cholesterol leaves the plaque, although flow into lymphatics is experimentally supported (Martel et al., 2013) and most consistent with physiological principles (Figure 3). Specifically, Martel et al. (2013) transplanted plaque-laden aortic arches that were loaded with stable isotope-cholesterol into atherogenic recipient mice. Inhibition of the regrowth of lymphatic vessels, by neutralizing anti-VEGFR3 mAb treatment, impaired the efflux of cholesterol from the transplanted aortic plaque tissue. Further study is warranted to delineate the nature of the lymphatic system involvement in RCT from native plaque in a less manipulated system. We propose that HDL accepts cholesterol from plaque macrophages and then exits via the lymphatic network, and that very few macrophages themselves exit the plaque via lymphatics (Potteaux et al., 2011; Randolph, 2014; Figure 3). As mentioned earlier, to better clarify these mechanisms, models are needed that can avoid some caveats, one of which is the inherent inflammation of the surgical procedure that can promote neo-lymphangiogenesis (Aebischer et al., 2014).


The role of the lymphatic system in cholesterol transport.

Huang LH, Elvington A, Randolph GJ - Front Pharmacol (2015)

Lymphatic dependent reverse cholesterol transport within the atherosclerotic plaque. In the context of the atherosclerotic plaque environment, removal of plaque cholesterol may be impaired by oxidation and modification of ApoA1 that prevents its ability to accept cholesterol from foam cells to form HDL. Movement of the HDL-cholesterol out of plaques occurs in the direction of interstitial fluid flow with removal likely occurring in adventitial lymphatic vessels.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557107&req=5

Figure 3: Lymphatic dependent reverse cholesterol transport within the atherosclerotic plaque. In the context of the atherosclerotic plaque environment, removal of plaque cholesterol may be impaired by oxidation and modification of ApoA1 that prevents its ability to accept cholesterol from foam cells to form HDL. Movement of the HDL-cholesterol out of plaques occurs in the direction of interstitial fluid flow with removal likely occurring in adventitial lymphatic vessels.
Mentions: The influx, oxidization, and retention of ApoB-containing lipoproteins within the subendothelial space is a key aspect of the initiation of atherosclerosis (Tabas et al., 2007). Recruitment of monocytes, and differentiation into foamy macrophages, drive disease progression (Gautier et al., 2009). As macrophages phagocytize oxidized ApoB-containing lipoproteins, a fatty streak is formed within the intimal layer of the vessel, serving as a marker for the early stage of disease. Foam cells are thought to be inflammatory and necrosis of macrophages alongside invading smooth muscle cells with altered differentiation (Shankman et al., 2015) result in the formation of necrotic core and cholesterol crystals (Glass and Witztum, 2001). Is there a role for lymphatic vessels in plaque progression? A relationship between atherosclerosis and reduced lymphatic transport of cholesterol was hypothesized in the early 1980s (Lemole, 1981; Miller et al., 1992). Lymphatic vessels were later identified within the arterial wall (Johnson, 1969; Nakano et al., 2005; Drozdz et al., 2012). In human diseased vessels, a positive correlation exists between intimal thickness and adventitial lymphatic density (Drozdz et al., 2008), as well as lymphatic dysfunction and atherogenesis (Eliska et al., 2006). Perhaps these results can be interpreted as evidence that lymphatics remodel to facilitate RCT from the intimal environment. It remains unclear and imperfectly studied as to how HDL cholesterol leaves the plaque, although flow into lymphatics is experimentally supported (Martel et al., 2013) and most consistent with physiological principles (Figure 3). Specifically, Martel et al. (2013) transplanted plaque-laden aortic arches that were loaded with stable isotope-cholesterol into atherogenic recipient mice. Inhibition of the regrowth of lymphatic vessels, by neutralizing anti-VEGFR3 mAb treatment, impaired the efflux of cholesterol from the transplanted aortic plaque tissue. Further study is warranted to delineate the nature of the lymphatic system involvement in RCT from native plaque in a less manipulated system. We propose that HDL accepts cholesterol from plaque macrophages and then exits via the lymphatic network, and that very few macrophages themselves exit the plaque via lymphatics (Potteaux et al., 2011; Randolph, 2014; Figure 3). As mentioned earlier, to better clarify these mechanisms, models are needed that can avoid some caveats, one of which is the inherent inflammation of the surgical procedure that can promote neo-lymphangiogenesis (Aebischer et al., 2014).

Bottom Line: Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream.There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels.New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO, USA.

ABSTRACT
Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

No MeSH data available.


Related in: MedlinePlus