Kenneth M. DeSart, MD, Khayree Butler, MD, Kerri A

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Presentation transcript:

Time and flow-dependent changes in the p27kip1 gene network drive maladaptive vascular remodeling Kenneth M. DeSart, MD, Khayree Butler, MD, Kerri A. O'Malley, PhD, Zhihua Jiang, PhD, Scott A. Berceli, MD, PhD Journal of Vascular Surgery Volume 62, Issue 5, Pages 1296-1302.e2 (November 2015) DOI: 10.1016/j.jvs.2014.05.015 Copyright © 2015 Terms and Conditions

Fig 1 Vein graft flow rates and histologic analyses. A, After outflow branch ligation, an eightfold difference in flow rates was observed across all time points in low-flow (dashed line) and high-flow (dotted line) grafts (P < .001). B, A significant increase in intimal area was noted by 7 days in the low-flow (dashed line) vs high-flow (dashed line) grafts (0.13 ± 0.04 mm2 vs 0.014 ± 0.006 mm2; P < .005). By 28 days, a striking difference in intimal area was observed between high-flow and low-flow grafts (1.37 ± 0.05 mm2 vs 0.39 ± 0.06 mm2; P < .001). C, At 7 days, low-flow (dashed line) grafts demonstrated a burst of actively dividing intimal and medial cells compared with high-flow (dotted line) grafts (36.4 ± 9.4 vs 11.5 ± 1.9 cells/mm2 positive for bromodeoxyuridine [BrdU]; P = .04), correlating with the period of significant intimal expansion. D, No differences in luminal diameter were observed between high-flow (dotted line) and low-flow (dashed line) vein grafts. The range bars show the standard error. E, Representative Masson trichrome-stained cross-sections extending from the external elastic lamina to the intima demonstrate robust intimal expansion in low-flow vein grafts (original magnification ×40). Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions

Fig 2 Analysis of 34 probe sets demonstrating a significant change in expression over time after vein graft placement. A, Supervised hierarchal clustering analysis of the 34 time-dependent probe sets (false discovery rate = .05) reveals two distinct clusters with differential expression patterns. Mean expression data at each time point and flow condition are presented across the x-axis, with red representing upregulation and blue representing downregulation. Cluster A consists of 18 genes that exhibit early upregulation at 2 hours and 1 day, whereas cluster B consists of eight genes that exhibit late upregulation, particularly at 7 days. B, Cluster A expression patterns are similar for high-flow and low-flow grafts. C, Cluster B reveals differences in graft recover between flow states, with the high-flow grafts exhibiting prolonged upregulation. The gray dashed lines represent the mean expression fold change from baseline (normal vein) of each individual probe set for a given cluster and flow condition. The solid black line represents the mean expression fold change (from baseline) of all probe sets for a given cluster and flow condition. Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions

Supplementary Fig 1 (online only) Bromodeoxyuridine (BrdU) cell proliferation assay. Representative full-thickness sections from each time point and flow condition are displayed. Proliferating cells in the neointima and media were quantified. A significant burst of BrdU-positive cells was observed in low-flow grafts at 7 days (original magnification ×10). Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions

Supplementary Fig 2 (online only) Masson trichrome stained low-flow vein grafts. All low-flow vein grafts were patent and free of thrombus at the time of harvest. To preserve messenger RNA integrity, grafts were not perfusion fixed at the time of harvest, resulting in the collapsed appearance of the thin-walled early time point samples. Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions

Supplementary Fig 3 (online only) Unsupervised hierarchal clustering analysis of 34 probe sets demonstrates a significant temporal change in expression after vein graft placement. Individual vein graft samples at each time point and flow condition are displayed across the x-axis. The horizontal dendrogram reveals that samples tend to cluster by time point rather than by flow condition. Also note the 28-day samples cluster with the time 0 controls at the right side of the heat map, indicating a relative return to baseline gene expression by 28 days. Red represents upregulation, and blue represents downregulation. Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions

Supplementary Fig 4 (online only) Unsupervised hierarchal clustering analysis using averaged expression data of 34 probe sets demonstrates a significant change over time. Mean expression data at each time point and flow condition are presented across the x-axis. The horizontal dendrogram displays a nearly perfect clustering by time point, again highlighting time as the dominant factor driving gene expression after graft implantation. Red represents upregulation and blue represents downregulation. Journal of Vascular Surgery 2015 62, 1296-1302.e2DOI: (10.1016/j.jvs.2014.05.015) Copyright © 2015 Terms and Conditions