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Ferrata Storti Foundation
Hematopoiesis
Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis
Annas Al-Sharea,1* Man K. S. Lee,1 Alexandra Whillas,1 Danielle L. Michell,1,2 Waled A. Shihata,1,3 Alyce J. Nicholls,4 Olivia D. Cooney,1 Michael J. Kraakman,1,5 Camilla Bertuzzo Veiga,1 Ann-Maree Jefferis,3 Kristy Jackson,6 Prabhakara R. Nagareddy,7 Gavin Lambert,8,9 Connie H. Y. Wong,4
Haematologica 2018 Volume 104(3):456-467
Karen L. Andrews,3 Geoff A. Head,6 Jaye Chin-Dusting3 and Andrew J. Murphy1,10*
1Haematopoiesis and Leukocyte Biology Laboratory, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; 2Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; 3Department of Pharmacology, Monash University, Clayton, VIC, Australia; 4Monash University, Melbourne, VIC, Australia; 5Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY, USA; 6Neuropharmacology Laboratory, Division of Hypertension and Cardiac Disease, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; 7Department of Nutrition Sciences, University of Alabama at Birmingham, AL, USA; 8Human Neurotransmitters Laboratory, Division of Hypertension and Cardiac Disease, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; 9Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia; 10Department of Immunology, Monash University, Melbourne, VIC, Australia
*Corresponding Authors
ABSTRACT
Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular dis- ease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allow- ing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic acti- vation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothe- lial cells and osteoblasts. Additionally, sympathetic bone marrow activi- ty prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the b-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sym- pathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to car- diovascular events.
Introduction
Hypertension is a major, independent risk factor for atherosclerotic cardiovascu- lar disease (CVD).1 As the pathophysiology of hypertension is both complex and multifactorial, the direct mechanism(s) that ultimately contribute to CVD remain
Correspondence:
ANDREW J. MURPHY
andrew.murphy@baker.edu.au
ANNAS AL-SHAREA
annas.al-sharea@baker.edu.au
Received: March 7, 2018. Accepted: October 22, 2018. Pre-published: October 25, 2018.
doi:10.3324/haematol.2018.192898
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/456
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