New determinants of the uptake of atherogenic plasma proteins by arteries.

Atherosclerotic disease begins with the accumulation of atherogenic plasma proteins, predominantly low-density lipoprotein (LDL), in susceptible arteries. One determinant of this is the LDL concentration in the blood (4). We are investigating other factors which may influence the uptake of LDL and of fibrinogen, another atherogenic plasma protein, by artery walls, as well as the mechanism(s) of this uptake. In order to model human atherogenesis as closely as possible, the experiments are mostly in vivo, using rabbits and rats. In anesthetized rabbits, intravenous infusions of histamine sufficient to produce interendothelial gaps throughout the venular systems did not increase the rate constant of the disappearance of LDL from the circulating blood. This makes it improbable that significant quantities of LDL pass out of the blood into vessel walls between endothelial cells, and it indirectly supports the evidence that LDL leaves the plasma by transcytosis through the endothelial cells. In anesthetized rabbits and in conscious rats the uptake of LDL, methylated to prevent its removal by high-affinity receptors (m-LDL), is significantly increased by noradrenaline and by adrenaline at their pathophysiological blood concentrations. In man this could help to account for the coronary risk factor status of cigarette smoking, hypertension, stress, etc. when associated with increases in circulating catecholamines. The mechanism of this effect is now under investigation.