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. 2017 Jan;79(1):59-70.
doi: 10.1097/PSY.0000000000000360.

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

Crystal M Noller  1 , Armando J Mendez, Angela Szeto, Marcia Boulina, Maria M Llabre, Julia Zaias, Neil Schneiderman, Philip M McCabe
Affiliations

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

Crystal M Noller et al. Psychosom Med. 2017 Jan.

Abstract

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.

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Conflict of interest statement

Authors report no conflicts of interest. Conflicts of Interest and Sources of Funding:

Figures

Figure 1
Figure 1
Identification of intima and media in rabbit aortic sections. Tissues were stained with DAPI to identify areas of cellularity for a NZW (A) or WHHL (B) rabbits. Delineation of Media and Intima or Neo-intima, outlined in white, was identified by the border of the inter-elastic lamina.
Figure 2
Figure 2
Identification of aortic sympathetic varicosities in WHHL rabbit. (A) Synapsin immunofluorescence shown in red, (B) TH shown in green, and (C) merge of A and B showing colocalization (seen as yellow), indicative of sympathetic varicosities. Panels D, E and F show primary antibody isotype controls for panels A, B and C, respectively. Confocal images were obtained with a 40X objective lens.
Figure 3
Figure 3
Representative 40X confocal images (selected from 24 NZWs and 22 WHHLs; 3 slides per animal) showing SNS varicosities in rabbit aortic arch. (A, C) NZW and WHHL aortas, respectively, showing co-localization of TH and Synapsin (yellow), (B, D) enlargement of insets from panels A and C that includes nuclear stain (DAPI, blue). White line in panel C and D indicate border between vascular media and atherosclerotic lesion (neointima), whereas in panels A and B there is no disease (neointima) in the NZWs. Note dense SNS varicosities in the vascular media in both rabbit strains, and extensive SNS innervation of the neointima in the WHHL.
Figure 4
Figure 4
Sympathetic innervation density in the thoracic aortic and aortic arch of NZW (n =24) and WHHL (n = 22) rabbits. Box plot (highlighting 5th, 25th, median, 75th, and 95th percentile of the data) of innervation density was measured in cross sectional aortic sections from each rabbit strain, and number of varicosities were expressed as counts/total aortic area (mm2). There was greater innervation density in WHHLs relative to NZWs in the aortic arch and thoracic aorta (both comparisons, p < 0.01).
Figure 5
Figure 5
The relationship between the number of SNS varicosities and the intimal area of the aorta. (A, B) In the WHHLs, the number of intimal SNS varicosities increased as neointimal area expanded in the aortic arch ((r(21) = .855, p < .001) and thoracic aorta ((r(22) = .789, p < .001) due to atherosclerotic disease progression. (C, D) There was no relationship between the number of intimal varicosities and the intimal area for the NZWs that had virtually no disease.
Figure 6
Figure 6
Confocal immunohistochemical and light microscopic images of a representative WHHL aorta (selected from 22 WHHLs; 3 slides per animal). (A) 10X light microscopic image of H & E stained aorta in WHHL with extensive atherosclerosis (same animal as panels B-F), (B) 20X tiled image of tyrosine hydroxylase (TH, green) labeling (suggesting numerous SNS varicosities throughout the vessel, including the neointima), (C, D, E) 40X images of the area in the highlighted box in panel B showing TH (white), macrophages (RAM-11, red), and Nerve Growth Factor (NGF, green), respectively, (F) Merged 40X image showing SNS varicosities (TH, white), macrophages (RAM-11, red) and Nerve Growth Factor (NGF, green). In addition, nuclei were stained with DAPI (blue). The co-localization of macrophages and NGF appears as yellow. Note the co-localization of NGF and macrophages proximal to the TH-labeling, as well as the absence of TH-labeling within regions of necrosis (seen as dark areas devoid of staining).
Figure 7
Figure 7
SNS varicosities in mouse aortic arch (selected from 4 ApoE and 4 wildtype mice). (A, C) H & E stained wildtype and ApoE (−/−) mouse aortas, respectively. Note extensive atherosclerosis in the ApoE (−/−) aorta. (B, D) 40X confocal images of sections nearby the sections in panels A & C showing TH (green) and Synapsin (red) with co-localization appearing yellow in wildtype and ApoE (−/−) aortas, respectively. Note SNS varicosities in the media of both diseased and non-diseased aortas, and extensive varicosities in the atherosclerotic neointima of the ApoE (−/−) aorta.
Figure 8
Figure 8
SNS varicosities in a human aorta (selected from 4 human aortas) with evident atherosclerosis. 40X confocal image showing TH (green) and Synapsin (red) with co-localization appearing yellow. White line delineates the intimal-medial border. Note dense innervation in both the media and atherosclerotic neointima.
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