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Chan Woo Kim, PhD1,2*; Anastassia Pokutta-Paskaleva, PhD1,3*; Sandeep Kumar, PhD1*; Lucas H. Timmins, PhD4, 5; Andrew D. Morris, MD3; Dong-Won Kang, MS1; Sidd Dalal, BS6; Tatiana Chadid, MD3; Katie M. Kuo, BS3; Julia Raykin, PhD1; Haiyan Li, MD3; Hiromi Yanagisawa, MD, PhD7; Rudolph L. Gleason, Jr., PhD1,8; Hanjoong Jo, PhD1#; Luke P. Brewster MD, PhD1,3,9,10#
1 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA; 2Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea; 3Department of Surgery, Emory University, Atlanta, GA; 4Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA; 5Department of Bioengineering, University of Utah, Salt Lake City, UT; 6Mercer University School of Medicine, Macon, GA; 7 Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan; 8 George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA; 9Surgical and Research Services, Atlanta VA Medical Center, Decatur, GA; 10Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
*These authors contributed equally for this work.
#These authors are co-corresponding authors.
Addresses for Correspondence : Luke P. Brewster, MD, PhD, Hanjoong Jo, PhD
Abstract
Background - Arterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries.
Methods - D-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared to unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow (s-flow) were tested ex vivo to validate critical results from the animal model.
Results - D-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified that transforming growth factor-beta (TGF-β) pathways having a prominent role in this stiffened arterial response, but that this was due to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to TGF-β. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of TGF-β in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model.
Conclusions - TSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1's activation of TGF-β's profibrotic signaling pathways. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.
disturbed flow, thrombospondin-1, arterial compliance, arterial stiffness, shear stress
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