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Hemodynamic Influence on Smooth Muscle Cell Kinetics and Phenotype During Early Vein Graft Adaptation

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Abstract

Pathologic vascular adaptation following local injury is the primary driver for accelerated intimal hyperplasia and an occlusive phenotype. Smooth muscle cell (SMC) proliferation within the wall, and migration into the developing intima, is a major component of this remodeling response. The primary objective in the current study was to investigate the effect of the local biomechanical forces on early vein graft adaptation, specifically focusing on the spatial and temporal response of SMC proliferation and conversion from a contractile to synthetic architecture. Taking advantage of the differential adaptation that occurs during exposure to divergent flow environments, vein grafts were implanted in rabbits to create two distinct flow environments and harvested at times ranging from 2 h to 28 days. Using an algorithm for the virtual reconstruction of unfixed, histologic specimens, immunohistochemical tracking of DNA synthesis, and high-throughput transcriptional analysis, the spatial and temporal changes in graft morphology, cell proliferation, and SMC phenotype were catalogued. Notable findings include a burst of cell proliferation at 7 days post-implantation, which was significantly augmented by exposure to a reduced flow environment. Compared to the adjacent media, proliferation rates were 3-fold greater in the intima, and a specific spatial distribution of these proliferating cells was identified, with a major peak in the sub-endothelial region and a second peak centering on the internal elastic lamina. Genomic markers of a contractile SMC phenotype were reduced as early as 2 h post-implantation and reached a nadir at 7 days. Network analysis of upstream regulatory pathways identified GATA6 and KLF5 as important transcription factors that regulate this shift in SMC phenotype.

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Acknowledgments

This work was supported by funding from the National Institutes of Health (NIH-NHLBI U01-HL119178). The authors would like to thank Angela Cuenca for her efforts in performing the animal models used in this work.

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    Authors and Affiliations

    1. Malcom Randall VA Medical Center, Gainesville, FL, USA

      Benjamin Klein, Leanne Dumeny, Qiongyao Hu, Yong He, Kerri O’Malley, Zhihua Jiang & Scott Berceli

    2. Department of Surgery, University of Florida, Box 100128, Gainesville, FL, 32610-0128, USA

      Benjamin Klein, Leanne Dumeny, Qiongyao Hu, Yong He, Kerri O’Malley, Zhihua Jiang & Scott Berceli

    3. Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, USA

      Anthony Destephens & Roger Tran-Son-Tay

    4. Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

      Roger Tran-Son-Tay & Scott Berceli

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    Correspondence to Scott Berceli.

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    Associate Editor Scott I. Simon oversaw the review of this article.

    Benjamin Klein and Anthony Destephens have contributed equally to this work.

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    Klein, B., Destephens, A., Dumeny, L. et al. Hemodynamic Influence on Smooth Muscle Cell Kinetics and Phenotype During Early Vein Graft Adaptation. Ann Biomed Eng 45, 644–655 (2017). https://doi.org/10.1007/s10439-016-1725-0

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