Occurrence of stroke in a nonhuman primate model of cerebrovascular disease.

Abstract

A relation between hypertension, atherosclerosis, and stroke is well documented in humans. We report a similar relation in two hypertensive cynomolgus monkeys with severe cerebral atherosclerosis. In our primate model hypertension is induced by surgical coarctation of the aorta. These monkeys, when fed an atherogenic diet, develop severe cerebrovascular atherosclerosis. In this setting two monkeys developed spontaneous cerebral hemispheric strokes that occurred during treatment of hypertension. Since the strokes were topographically related to severe atherosclerotic narrowing of cerebral arteries and occurred without evidence of either thrombosis or embolization, they are presumed to be related to disturbances of blood flow. In both humans and animals cerebral perfusion is autoregulated to a constant flow over a wide range of mean arterial blood pressures. In hypertension both the upper and lower limits of autoregulation are increased. With treatment of hypertension readaptation to more normal levels is reported to be inconsistent and slow to develop. It is therefore postulated that the strokes in these two monkeys were due to hypoperfusion as a result of the combination of pharmacologic reduction in blood pressure and severe occlusive atherosclerosis. 4 reported severe cerebrovascular atherosclerosis when the monkeys were fed an atherogenic diet. We report two cases of spontaneous stroke in this monkey model of cerebrovascular atherosclerosis. These monkeys were part of a group of 16 similarly treated animals on a pharmacologic regimen to reduce elevated blood pressure. Within this group, these two monkeys showed severe cerebrovascular atherosclerosis and the most marked reduction in blood pressure, suggesting that antihypertensive medication played a role in their pathogenesis. Materials and MethodsBoth brains were embedded whole in celloidin and cut in gapless serial sections at a thickness of 35 /im. Every twentieth section was stained with Nissl's stain for tissue reactions and vascular pathology, and the adjacent section was stained with Loyez stain for myelinated fibers. The large arteries at the base of the brain and the extracranial internal carotid arteries were removed at the time of autopsy and visually inspected at a magnification of 2 x for atherosclerotic plaques, thrombi, and emboli. Representative sections from predetermined sites (all areas labeled in Figure 4) and Received January 23, 1987; accepted August 3, 1987. all grossly visible atherosclerotic plaques were embedded in polyethylene glycol with 4-/u.m-thick sections stained with oil red O, Verhoeff-van Gieson's stain, and toluidine blue. Morphometric measurements were performed on the histologic cross sections with a Zeiss MOP III Image Analyzer (Thornwood, New York). Lesion size or intimal area was determined by digitizing the area between the internal elastic membrane and the luminal surface of the artery. The percent stenosis (shown in Figure 4) is the maximum narrowing observed in all arteries showing atherosclerosis and was calcul...

Intracranial atherosclerotic disease: An update

“…There is increased insudation of fibrinogen and LDL‐cholesterol in the subendothelial spaces82 consistent with human pathological findings 83, 84. In cynomolgus monkeys, hypertension induced by surgical thoracic aorta coarctation and hypercholesterolemic diet for 12 months induces ICAD85 with associated ischemic strokes 86. Infiltration of lipid‐laden foam cells and lipid droplet–filled smooth muscle cells have been described in the basilar artery in this model 87.…”

Different Strokes for Different Folks: The Rich Diversity of Animal Models of Focal Cerebral Ischemia

“…To date, no stroke studies seem to have been undertaken in hypertensive transgenic rats expressing an extra copy of the renin gene (Wagner et al , 1997). Ischemic stroke has been induced in Cynomolgus monkeys made hypertensive by surgical coarctation of the aorta in animals fed an atherogenic diet (Prusty et al , 1988), but this would not seem to be a practical model for widespread use.…”

High fat and high fructose diet induced intracranial atherosclerosis and enhanced vasoconstrictor responses in non-human primate

“…In contrast to atherosclerosis found at peripheral regions, cerebral atherosclerosis appears particularly related to hypertension (Sadoshima et al, 1980). In addition, high fat diet and hypertension induced by surgical treatment caused intracranial atherosclerosis in cynomolgus monkeys (Prusty et al, 1988;Hollander et al, 1993) and rabbits (Kato et al, 1991). Unfortunately, we could not reliably measure the blood pressure under unanesthetized conditions in our study, because their blood pressure was found to be highly variable during our measurement period.…”

“…However, a high fat diet in combination with surgical interventions, such as a vasectomy (Alexander and Clarkson, 1978) or experimental hypertension by coarcting the thoracic aorta (Prusty et al, 1988), has been shown to effectively induce intracranial atherosclerosis in nonhuman primates.…”