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Structural Remodeling of Sympathetic Innervation in Atherosclerotic Blood Vessels: Role of Atherosclerotic Disease Progression and Chronic Social Stress

Noller, Crystal M. PhD; Mendez, Armando J. PhD; Szeto, Angela PhD; Boulina, Marcia PhD; Llabre, Maria M. PhD; Zaias, Julia DVM, PhD; Schneiderman, Neil PhD; McCabe, Philip M. PhD

doi: 10.1097/PSY.0000000000000360
Original Articles

Objective The sympathetic nervous system (SNS) can undergo dramatic structural plasticity in response to behavioral factors and/or the presence of disease, leading to SNS hyperinnervation of peripheral tissues. The SNS has been proposed as an important mediator between stressful behavior and the progression of atherosclerosis in the vasculature. The present study examined whether structural remodeling of the SNS occurs in the vasculature in a genetically hyperlipidemic animal model of atherosclerosis, the Watanabe heritable hyperlipidemic rabbit (WHHL; relative to normolipidemic New Zealand white rabbits [NZW]), and whether SNS plasticity is driven by the progression of disease and/or by stressful social behavior.

Methods WHHL and NZW rabbits were assigned to an unstable or stable social environment for 4 months. Aortic atherosclerosis was assessed and SNS aortic innervation quantified using immunofluorescent microscopy.

Results Numerous SNS varicosities were observed throughout the aorta in WHHLs and NZWs, extending into the vascular media and intima, an innervation pattern not previously reported. WHHLs exhibited significantly greater innervation than NZWs (F(1,41) = 55.3, p < .001), with extensive innervation of the atherosclerotic neointima. The innervation density was highly correlated with the extent of disease in the WHHLs (r(21) = 0.855, p < .001). Social environment did not influence innervation in NZWs (aortic arch: p = .078, thoracic aorta: p = .34) or WHHLs (arch: p = .97, thoracic: p = .61).

Conclusions The findings suggest that hyperinnervation is driven largely by the progression of disease rather than social environment. SNS innervation patterns observed in atherosclerotic human and mouse aortas were consistent with the rabbit, suggesting that SNS hyperinnervation of the diseased vessel wall is a general feature across mammalian species.

From the Department of Psychology (Noller, Szeto, Llabre, Schneiderman, McCabe), University of Miami, Coral Gables, Florida; Diabetes Research Institute (Mendez, Boulina) and Departments of Medicine and Pathology (Zaias), University of Miami Miller School of Medicine, Miami, Florida.

Address correspondence and reprint requests to Philip M. McCabe, PhD, Department of Psychology University of Miami, PO Box 248185, Coral Gables, FL 33124. E-mail:

Received for publication December 17, 2015; revision received April 4, 2016.

Copyright © 2017 by American Psychosomatic Society
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