Effects of Atherosclerosis and Regression of Lesions
Our studies address two aspects of atherosclerosis: vasospasm, and regression of atherosclerotic lesions. One goal of the studies is to understand the pathophysiology of vasospasm. The second goal is to determine whether vasomotor abnormalities of atherosclerotic arteries are corrected by regression of lesions.
The experimental model is cynomolgus monkeys which develop atherosclerotic lesions that closely resemble those occurring in humans. Monkeys also develop moderately severe lesions in coronary, carotid, and limb arteries. We usually study blood vessels in the limb, but have also studied the coronary and cerebral circulation.
Our studies indicate that vascular responses are altered by atherosclerosis, and these changes predispose to vasospasm. The most striking and consistent change is that constrictor responses to serotonin are potentiated by atherosclerosis. There is also modest potentiation of vasoconstrictor responses to thromboxane and endothelin, and modest impairment of vasodilator responses to ADP. Our studies in vitro and several others indicate that endothelium-dependent relaxation is impaired by atherosclerosis. It is likely but not proven, that impairment of endothelium-dependent relaxation contributes to augmentation of vasoconstrictor responses in vivo.
Platelets have received considerable attention as cellular mediators of vasospasm. Vascular responses to vasoactive substances released by platelets are altered by atherosclerosis to favor vasoconstriction: vasodilator responses to ADP are impaired, and vasoconstrictor responses to serotonin and thromboxane are potentiated. Infusion of Collagen produces vasodilatation in normal and atherosclerotic monkeys, but after several minutes, large arteries of atherosclerotic monkeys constrict. These studies support the hypothesis that platelets may contribute to spasm of atherosclerotic arteries.
Atherosclerotic lesions contain many leukocytes, which are predominantly monocyte-macrophages. These cells may contribute to the formation and progression of lesions. Recently, we have suggested that vasoactive products that are released by leukocytes may produce spasm in atherosclerotic arteries. Injection of fMLP, a peptide that activates leukocytes, produces constriction of large arteries in atherosclerotic monkeys, with little effect in normal monkeys. Our studies suggest that prostaglandin E2 may contribute to leukocyte-induced constriction of atherosclerotic arteries. Thus, activation of leukocytes, as well as platelets, may produce pronounced constriction of atherosclerotic arteries.
It is now generally accepted that vasospasm can produce myocardial ischemia, angina, and myocardial infarction. We have proposed, based on studies in monkeys, that vasospasm may also contribute to transient ischemic attacks, with amaurosis fugax, and non-occlusive mesenteric ischemia. Vasospasm may produce ischemia in situations where the degree of structural vascular obstruction is insufficient to account for ischemia.
Because plasma cholesterol concentratian can now be effectively reduced, there is strong incentive to examine hemodynamic consequences of regression of atherosclerotic lesions. Regression of lesions in monkeys is not accompanied by corresponding improvement in maximal vasodilator capacity, which is probably impaired by arterial fibrosis. In contrast, we have found that regression of atherosclerosis is accompanied by restoration of endothelium-dependent relaxation and abolition of hyperresponsiveness. We thus anticipate that vasospastic syndromes may respond to effective treatment of hyper-cholesterolemia.
KeywordsAtherosclerotic Lesion Atherogenic Diet Normal Monkey Transient Ischemic Attack Atherosclerotic Artery
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