Social behavior and gender in biomedical investigations using monkeys: studies in atherogenesis

We review the use of socially housed cynomolgus monkeys (Macaca fascicularis) in biomedical research with emphasis on studies of atherosclerosis, particularly in the two specific domains of atherosclerosis investigation for which nonhuman primates are especially well-suited as animal models: gender differences and psychosocial influences. We found that the presence of normal ovarian function prevented exacerbation of diet-induced coronary artery atherosclerosis in female monkeys. However, any manipulation or condition which impaired ovarian function tended to diminish or abolish this "female" protection. Among group-housed female monkeys, low social status was accompanied by ovarian dysfunction and, not surprisingly, by exacerbated coronary artery atherosclerosis as well. Surgical menopause (ovariectomy) also induced exacerbation of coronary atherosclerosis in monkeys, a situation which was prevented by estrogen replacement therapy. Conversely, pregnancy (a hyperestrogenic state) resulted in markedly diminished atherosclerosis. A somewhat different pattern of atherogenesis emerged among socially-housed males. Here, socially dominant animals developed exacerbated coronary artery atherosclerosis, but only under conditions of social stress (viz., disruption caused by periodic reorganization of social group membership). We hypothesized that exposure to repeated group reorganizations provoked activation of the sympathetic nervous system among dominant animals; in turn, the hemodynamic and metabolic concomitants of sympathetic activation may have damaged the coronary arteries of these monkeys, potentiating atherogenesis. To test this hypothesis, males were housed in unstable social groupings, with half of the monkeys administered a beta-adrenergic blocking agent (to attenuate heart rate and blood pressure responses to stress). The beta-blocker inhibited atherosclerosis, but only among those animals behaviorally predisposed to develop exacerbated lesions (i.e. dominant monkeys). These results support the view that monkeys are suitable research models of atherosclerosis, a disease that affects millions of humans.