Age-related neointimal hyperplasia is associated with monocyte infiltration after balloon angioplasty

Abstract

Carotid angioplasty is associated with adverse events in elderly patients; it is unclear whether this is related to an altered inflammatory axis. The carotid arteries of young (6 months) or aged (22-24 months) Fischer 344 rats were balloon injured. Aged rats had reduced lumen area (0.18 ± 0.03 vs 0.24 ± 0.01 mm(2), p = .02) and increased neointimal thickening (0.15 ± 0.04 vs 0.08 ± 0.03 mm(2), p = .006). Aged rats had increased circulating monocytes (96 ± 21 vs. 54 ± 7; p = .002) as well as increased numbers of monocytes at the post-angioplasty site. Aged rats had sustained monocyte chemotactic protein-1 expression after angioplasty but young rats did not. Aged arteries also exhibited defective vasorelaxation and abnormal eNOS localization. Aged (≥80 years) human patients with high-grade carotid stenosis had increased number of monocytes (9.1% ± 0.4%) compared with younger (65-80 years) patients (8.1% ± 0.3%, p = .013). Aged rats develop neointimal hyperplasia after carotid angioplasty with increased numbers of monocytes, and elderly humans with carotid stenosis have increased numbers of circulating monocytes. These preliminary results may suggest a role for monocytes in the response to carotid angioplasty.

Figure 1.

Effect of balloon angioplasty in young and aged Fischer 344 rats. (A) Representative photomicrographs, low, and high magnification of young and aged carotid arteries, both control arteries and arteries 2 weeks after balloon angioplasty. H&E, hematoxylin and eosin; MT, Masson’s trichrome. (B) Bar graph of vessel area in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 5–6; *p < .05. (C) Bar graph of lumen area in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 5–6; *p = .02. (D) Bar graph of intimal thickness in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 5–6; *p = .006.

Figure 2.

Effect of balloon angioplasty on SMC in young and aged Fischer 344 rats. (A) Representative photomicrographs, low, and high magnification of young and aged carotid arteries, both control arteries and arteries 2 weeks after balloon angioplasty. SMA, smooth muscle actin; MHC, myosin heavy chain. Arrowheads show presence of MHC reactivity. (B) Bar graph of intimal alpha-actin density in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 5–6; *p < .0001, #p = .002. (C) Bar graph of medial alpha-actin density in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 5–6; *p = .03. (D) Bar graph of Ephrin-B2 relative transcription level in young and aged carotid arteries in response to balloon angioplasty (2 weeks). Error bars denote SEM; n = 8; p = .08, p = .07 for reduction in post-angioplasty groups versus control in aged arteries. A.U., arbitrary units.

Figure 3.

Effect of balloon angioplasty on monocytes in young and aged Fischer 344 rats. (A) Representative photomicrographs of young and aged carotid arteries, 3 days after balloon angioplasty. Arrowheads show presence of F4/80 reactivity. (B) Bar graph of MCP-1 expression in young and aged carotid arteries in response to balloon angioplasty. Error bars denote SEM; n = 8. The difference between young and aged arteries is significant (p = .05, analysis of variance), both at control and Day 14 (p = .01, post hoc test). (C) Bar graph of CCR-2 expression in young and aged carotid arteries in response to balloon angioplasty. Error bars denote SEM; n = 8. The difference between young and aged arteries is significant (p = .01, analysis of variance), at Day 14 (p = 0.03, post hoc test) but not Day 3 (p = .41).

Figure 4.

Abnormal endothelial function in aged arteries. (A) Vasoconstriction of uninjured young and aged arteries in response to phenylephrine (PE). Error bars denote SEM; n = 3. The difference between young and aged arteries is not significant (p = .47, paired t test). (B) Vasorelaxation of uninjured young and aged arteries in response to acetylcholine (Ach). Error bars denote SEM; n = 3. The difference between young and aged arteries is significant (p = .01, paired t test). (C) Representative photomicrographs of uninjured young and aged carotid arteries examined en face with immunofluorescence; n = 3.