The carotid sinus is unusually susceptible to development of severe atherosclerotic lesions. The purposes of this study were to examine effects of atherosclerosis on blood flow through vasa vasorum in the carotid sinus and to examine responses to humoral stimuli. Blood flow to vasa in the carotid sinus was measured with microspheres in 8 normal and 9 atherosclerotic cynomolgus monkeys. Blood flow to vasa in intima-media (in ml/min per 100 g) was 0.5 +/- 0.3 (mean +/- SE) in normal and 21 +/- 5 in atherosclerotic monkeys (P less than 0.05). Flow to adventitial vasa was 37 +/- 5 in normal monkeys and 50 +/- 7 in atherosclerotic monkeys (P greater than 0.05). Infusion of phenylephrine did not affect blood flow in normal or atherosclerotic monkeys. Infusion of serotonin did not affect blood flow to vasa in normal monkeys, but decreased flow to vasa in both intima-media and adventitia of atherosclerotic monkeys. In normal media, histological examination demonstrated the presence of a few vasa vasorum, which penetrated from adventitia. In atherosclerotic monkeys, medial vasa were much more frequent. Thus, (1) atherosclerosis produces marked increases in blood flow through vasa in intima-media of the carotid sinus, probably as a consequence of proliferation of vasa, and (2) in atherosclerotic monkeys, vasa constrict in response to serotonin. Based on these findings, we speculate that when serotonin is released as platelets aggregate at plaques in the carotid artery, serotonin may be delivered through vasa to nerves in the carotid sinus and thereby affect baroreceptor function.