Role of dying endothelial cells in transendothelial macromolecular transport.

Abstract

There are focal areas in the aorta wtth an enhanced endothelial permeability to macromolecules, as indicated by the focal uptake of the proteln-blndlng azo dye Evans blue In vivo. These areas exhibit high rates of endothelial cell turnover and a number of structural characteristics In en face endothelial morphology. To determine the relationship of endothelial cell death to macromolecular leakage at the level of individual endothelial cells, thoracic aortas of 12 adult male Sprague-Dawley rats were studied at 3 to 5 minutes after Intravenous administration of Evans blue-albumin ( 1 In previous studies, 2 -5 we demonstrated that an extremely high percentage of dividing endothelial cells in the mitotic M phase exhibited junctional leakage to macromolecules, i.e., 91 % for Evans blue-albumin (EBA) and 78% for Lucifer yellow-tow density lipoprotein (LY-LDL), but these mitotic endothelial cells with tracer leakage contributed to only 23% of all EBA leaky foci and 42% of all LY-LDL leaky foci. Thus, mitotic endothelial cells alone cannot explain all the macromolecular leaks observed in the aorta.A small, but significant, fraction of endothelial cells can be found to undergo turnover in normal rat aortic endothelium.8 Studies by Hansson et al. 6 have shown that endothelial cell death and replication are topographically clustered phenomena. There seems to be a spatial association between clusters of dead endothelial cells and clusters of replicating endothelial cells. The codistribution of dead and replicating cells in the aortic endothelium suggests that, in adult animals, the role of

Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell

“…These findings have led to the hypothesis that complex flow patterns cause an accelerated EC turnover (including cell mitosis and death), such that the resulting leaky junctions between the ECs undergoing turnover cause an increase in the permeability of large molecules (e.g., LDL) across the endothelial layer (79). Our experimental studies have provided evidence that EC mitosis (12,44) and death (42) are associated with the leakage of macromolecules such as LDL and albumin on an individual cell basis. Studies performed in a number of laboratories, including our own, have shown that these events of accelerated EC turnover occur primarily in areas with disturbed blood flow, e.g., arterial branch points (15,43,60,72).…”

Computational modeling of coupled blood-wall mass transport of LDL: effects of local wall shear stress

“…Various experimental (2,19,21,37,38) and computational (1, 13-15, 25, 31, 33, 40) studies have been conducted to comprehend the pathways and mechanisms governing LDL transport from the artery lumen into the arterial wall and within the arterial wall. There are two pathways of LDL transport through the endothelium: by vesicular transcytosis, which is regulated by receptors on the endothelial cells (30), and through leaky junctions, most of which are located at the sites of dying or replicating cells (18,19).…”

In vitro study of LDL transport under pressurized (convective) conditions

“…Examination of animal tissue using electron microscopy following incubation with LDL has revealed the presence of vesicles containing LDL within cells that may deliver lipoproteins across the endothelium via transcytosis (28,31). Other studies have shown that cells in a state of turnover can allow large macromolecules, including LDL and albumin, to cross the endothelium through so-called "leaky junctions" (15)(16)(17)33). Little work has probed the transport of LDL across cultured endothelial monolayers that may serve as models for understanding and controlling transendothelial transport of LDL.…”