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Author Notes:

Luke P. Brewster, MD, PhD, Assistant Professor of Surgery, Emory University; Division of Vascular Surgery, Staff Surgeon, Atlanta VA Medical Center; Surgical and Research Services, Emory University School of Medicine, 101 Woodruff Circle, WMB Suite 5105, Atlanta, GA, 30322, lbrewst@emory.edu; luke.brewster@va.gov, F) 404 727-3660; O) 404 7278329; twitter) @dr_brewster.

Hanjoong Jo, PhD, John and Jan Portman Professor, Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, 1760 Haygood Drive, E170 HSRB, Atlanta, GA 30306, hjo@emory.edu;, F) 404 727-9873; O) 404 712-9136

Part of this work was recognized with the Jay D. Coffman Early Career Investigator Award by the PVD council of the American Heart Association and presented as an oral presentation at the 2014 American Heart Association’s Scientific Sessions in Chicago, IL, USA.

The authors would also like to thank Sebastian Perez from Emory University’s Department of Surgery for his assistance with the statistical analysis of this work.

Dr. Brewster has received significant compensation from his NIH KO8 award discovering the role of thrombospondin-1 in flow mediated arterial remodeling.

There are no other relevant disclosures among the authors.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • disturbed flow
  • thrombospondins
  • vascular stiffness
  • GROWTH-FACTOR-BETA
  • TGF-BETA
  • CARDIOVASCULAR EVENTS
  • NEOINTIMA FORMATION
  • MAJOR ACTIVATOR
  • STIFFNESS
  • CD47
  • HYPERTENSION
  • ORGANIZATION
  • ENDOTHELIUM

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1

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Journal Title:

Circulation

Volume:

Volume 136, Number 13

Publisher:

, Pages 1217-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 American Heart Association, Inc.

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