Endothelial injury and atherosclerosis

Abstract

In previous work, it has been shown that continued or repeated injury to the intima of arterial vessels in normal rabbits causes a spectrum of atherosclerotic lesions which include raised atheroma-containing plaques, fatty streaks, and fibromusculo-elastic plaques. On removal of the injurious stimulus, these lesions regressed rapidly, the residuum being a non-lipid-containing fibro-musculo-elastic plaque. The development of raised lipid-containing lesions can be markedly inhibited by making the rabbits thrombocytopenic with antiplatelet serum or a combination of Busulphan and antiplatelet serum. This indicates that the thrombotic process which accompanies repeated intimal injury, plays a key part in the development of lipid-containing lesions. Similarly, the fibro-musculo-elastic intimal thickening that follows a single removal of the endothelial layer of the rabbit aorta by balloon embolectomy catheter can also be markedly inhibited by exposing the rabbits to antiplatelet serum which induces severe thrombocytopenia. Taken together, these findings indicate that repeated damage to the endothelium might be an important mechanism by which lipid-containing raised lesions are induced. To examine this more closely in terms of a specific endothelial injury, the endothelium of rabbit aortas was removed six times at 2-week intervals employing a balloon embolectomy catheter. Animals killed at 1, 3, and 7 weeks following the last balloon injury showed preferential accumulation of lipid in intimal plaques covered by regenerated endothelium around aortic branches. In animals killed 6 months or 1 year following the last ballooning, lipid was seen preponderantly where the endothelium had regenerated from the orifices of aortic branches. The lesions resembled human fibro-fatty plaques or fatty streaks. In the areas where endothelial regeneration had not occurred, lipid was infrequently observed. The accumulation of lipid may relate to binding of lipoprotein to proteoglycans formed in the areas where the endothelium is repeatedly removed and regenerates.