The role of mitosis in LDL transport through cultured endothelial cell monolayers

Abstract

Cancel LM, Tarbell JM. The role of mitosis in LDL transport through cultured endothelial cell monolayers. Am J Physiol Heart Circ Physiol 300: H769 -H776, 2011. First published December 17, 2010 doi:10.1152 doi:10. /ajpheart.00445.2010 have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for Ͼ90% of the transport. We (8) have also recently shown that the permeability of bovine aortic endothelial cell monolayers is highly correlated with their rate of apoptosis and that inhibiting apoptosis lowers the permeability of the monolayers to LDL. To explore the role of mitosis in the leaky junction pathway, the microtubule-stabilizing agent paclitaxel was used to alter the rate of mitosis, and LDL flux and water flux (Jv) were measured. Control monolayers had an average mitosis rate of 0.029%. Treatment with paclitaxel (2.5 M) for 1.5, 3, 4.5, or 6 h yielded increasing rates of mitosis ranging from 0.099% to 1.03%. The convective permeability of LDL (P e) increased up to fivefold, whereas Jv increased up to threefold, over this range of mitosis rates. We found strong correlations between the mitosis rate and both P e and Jv. However, compared with our previous apoptosis study (8), we found that mitosis was only half as effective as apoptosis in increasing P e. The results led us to conclude that while mitotsis-related leaky junctions might play a role in the initial infiltration of LDL into the artery wall, the progression of atherosclerosis might be more closely correlated with apoptosisrelated leaky junctions.low-density lipoprotein permeability; bovine aortic endothelial cells; water flux; leaky junctions; mitosis THE FIRST EVENT in the cascade of processes leading to atherosclerotic lesion formation is lipid infiltration and accumulation within the arterial wall (41). A relationship between enhanced endothelial permeability to LDL and the localization of atherosclerotic plaques is well established (16, 33). There are three potential pathways for the transport of macromolecules across the endothelium: transcytosis in vesicles, paracellular transport through breaks in the tight junction strand, and the leaky junction pathway associated with cells undergoing mitosis or apoptosis. Previous in vivo (13, 28, 29) and theoretical (48) studies have supported the importance of the leaky junction pathway in LDL and albumin transport across the endothelium. In studies by Lin et al. (30) and Chien et al. (13), aortic sections were stained with hematoxylin to identify cells in the M phase of the cell cycle using morphological criteria. Roughly 1 in 3,000 cells was found to be mitotic, but nearly all of those had an Evans blue-albumin (EBA) or Lucifer yellow (LY)-LDL leakage spot associated with it (99% for EBA and 80% for LY-LDL). Mitotic cells accounted for 30% of all EBA leaks and 45% of all LY-LDL leaks.Observations that hemodynamic factors usually associated with the development of atherosclerosis also affect end...

Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI

“…Traction forces between cells and between the cell and substrate were larger on stiffer substrates, so that substrate stiffening promotes gap formation between ECs, thus disrupting the overall monolayer cohesion (25). Such stiffness-dependent changes of endothelium integrity would play a central role in atherosclerotic lesion and plaque development since leaky junctions within the EC monolayer are highly correlated with increased permeability to LDL transport (5).…”

Fluid Mechanics, Arterial Disease, and Gene Expression

“…Weinbaum et al (1985) hypothesized that leaky junctions around cells in a state of apoptosis or mitosis provide the major pathway for transport of large molecules such as LDL across the endothelium. More recent studies have shown a strong correlation between apoptosis and mitosis rates and LDL permeability of endothelial monolayers in culture (Cancel & Tarhell 2010, 2011). These studies, and others (reviewed in Tarbell 2003, 2010), suggest that chronic differences in shear stress do affect LDL transport into the vessel wall and that low shear stress may be expected to increase LDL permeability.…”

Mass Transport of Low Density Lipoprotein in Reconstructed Hemodynamic Environments of Human Carotid Arteries: The Role of Volume and Solute Flux Through the Endothelium

“…LDL particles, which are carried with blood flow in the lumen, may attach to the endothelial cell surface via LDL receptors and then can be transferred to the subendothelial layer by vesicles through the process of vesicular transcytosis. However, the portion of LDL passage via this mechanism is under 10%, in contrast to over 90% of LDL particles passing through cellular leakage which is formed by the detachment of endothelial cells [7,9,10]. Higher detachment rates are caused by elevated apoptosis and mitosis of cells under low or oscillatory WSS conditions, often referred to as "disturbed flow."…”

“…Leaky junctions are formed by the detachment of adjacent endothelial cells due to apoptosis and mitosis of the cell. The role of leaky junctions has been demonstrated in in vitro experiments [9,10] where an endothelial cell layer was coated on a porous medial structure. When an increase of apoptosis and mitosis rate was induced, it was found that the volume flux of blood plasma and solute flux of LDL increased linearly with the rate of endothelial cell apoptosis and mitosis.…”