Neovascularization Induced by the Cellular Component of Atherosclerotic Plaque
Small blood vessels, derived from vasa vasorum, are abundant in regions of atherosclerotic plaques but absent in normal inner media and intima. These fragile vessels are prone to rupture and may be the source of intraplaque hemorrhages. Intraplaque hemorrhages are characteristically found in symptomatic plaques and could lead to the acute complications of platelet emboli, arterial dissection, and thrombosis.
To determine what stimulates the growth of these new blood vessels, we tested the ability of atherosclerotic plaques to induce neovascularization. Nine atherosclerotic plaques from nine consecutive endarterectomies for symptomatic carotid stenosis were studied. The tissues were cut into 249 fragments with an average size of 1 mm3 and implanted into corneal micropockets of 2.5-kg male New Zealand white rabbits—a standard bioassay for angiogenesis. A positive response was defined as a sustained growth of capillaries, appearing within 72 hr, from the limbal plexus toward the implants. A negative response was indicated by the absence of blood vessels in the cornea adjacent to the implants. We used a stereomicroscope for daily observations. Eight days after implantation the rabbits were sacrificed, and the corneas were dissected and prepared for routine histological study of hematoxylin-and eosin-stained sections. The sections were evaluated for both the histology of the plaque fragments and the adjacent capillary growth within the corneal stroma. The plaque fragments were divided into cellular and non-cellular. A section was defined as cellular if one-third or more of the area contained more than 100 cells per high-power field (400 × ); a noncellular section had a low cell density, fewer than 100 cells per high-power field overall, or high cell density in only a small portion (less than one-third) of the section.
Forty-six percent of the implants (114/249) induced neovascularization. However, the histological study showed that 78% of 114 plaque fragments that were defined as cellular, characterized by many smooth muscle cells and some foam cells surrounded by collagen and elastic laminae, induced angiogenesis. In contrast, only 17% of the 116 noncellular plaque fragments that contained mainly necrotic, amorphic areas with calcification and cholesterol crystal clefts induced a positive response.
These results suggest that the smooth muscle cells, as the main cell type noted in the plaque fragments, are the source of an angiogenic factor. Normal arterial smooth muscle cells produce inhibitors of neovascularization. We suggest that in atherosclerosis the normal balance of stimulators and inhibitors is disnipted, and the stimulators for neovascularization predominate. The new blood vessels, formed as a result of the angiogenic activity, are prone to leak and rupture. This may lead to intraplaque hemorrhages that convert a clinically silent plaque to a symptomatic one.
KeywordsAtherosclerotic Plaque Carotid Stenosis Carotid Plaque Corneal Stroma Arterial Smooth Muscle Cell
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- Gimbrone, M. A., Jr., and Gullino, P. M., 1976, Neovascularization induced by intraocular xenografts of normal, preneoplastic, and neoplastic mouse mammary tissues, J. Natl. Cancer Inst. 56:305– 318.Google Scholar
- Higginbotham, A. C., Higginbotham, F. H., and Williams, T. W., 1963, Vascularization of blood vessel walls, in: Evolution of the Atherosclerotic Plaque (R. J. Jones, ed.), University of Chicago Press, Chicago, pp. 265-211.Google Scholar