Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1

• Type of Material: Article
• Authors: Chan Woo Kim, Georgia Institute of Technology; Anastassia Pokutta-Paskaleva, Georgia Institute of Technology; Sandeep Kumar, Emory University; Lucas Timmins, Emory University; Andrew D. Morris, Emory University; Don-Won Kang, Georgia Institute of Technology; Sidd Dalal, Mercer University; Tatiana Chadid, Emory University; Katie M. Kuo, Emory University; Julia Raykin, Georgia Institute of Technology; Haiyan Li, Emory University; Hiromi Yanagisawa, University of Tsukuba; Rudolph L. Gleason, Jr., Georgia Institute of Technology; Hanjoong Jo, Emory University; Luke Packard Brewster, Emory University
• Language: English
• Date: 2017-09-26
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026361
• Title of Journal or Parent Work: Circulation
• ISSN: 0009-7322
• Volume: 136
• Issue: 13
• Start Page: 1217
• End Page: +
• Grant/Funding Information: Funding for this work was provided by NIH: KO8HL119592 (LB), HL119798 and HL124879 (HJ); The Society for Vascular Surgery/American College of Surgeons Mentored Clinical Scientist Research Career Development Award (LB); American Heart Association, IRG1470001 (LB); and Departmental Support from Emory University Department of Surgery (Dr. John F. Sweeney) to Luke Brewster; and the Emory University School of Medicine; and Georgia Institute of Technology to Hanjoong Jo, the John and Jan Portman Professor of Biomedical Engineering.
• Keywords: disturbed flow; GROWTH-FACTOR-BETA; CD47; NEOINTIMA FORMATION; ORGANIZATION; thrombospondins; Cardiac & Cardiovascular Systems; Life Sciences & Biomedicine; TGF-BETA; ENDOTHELIUM; MAJOR ACTIVATOR; CARDIOVASCULAR EVENTS; Science & Technology; Peripheral Vascular Disease; STIFFNESS; vascular stiffness; HYPERTENSION; Cardiovascular System & Cardiology
• Research Categories: Engineering, Biomedical; Health Sciences, Radiology; Health Sciences, Medicine and Surgery

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 with unmanipulated carotid arteries from 80-weekold 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 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 transforming growth factor-β pathways as having a prominent role in this stiffened arterial response, but this was attributable to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to transforming growth factor-β. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of transforming growth factor-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 the profibrotic signaling pathways of transforming growth factor-β. 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.