Author Affiliations
- Annas Al-Sharea1,*,
- Man K. S. Lee1,
- Alexandra Whillas1,
- Danielle Michell2,
- Waled Shihata1,
- Alyce J Nicholls3,
- Olivia D Cooney1,
- Michael J Kraakman4,
- Camilla Bertuzzo Veiga1,
- Ann-Maree Jefferis3,
- Kristy Jackson1,
- Prabhakara R Nagareddy5,
- Gavin Lambert6,
- Connie H. Y Wong3,
- Karen L Andrews3,
- Geoff A Head1,
- Jaye Chin-Dusting3 and
- Andrew J Murphy1
- 1 Baker Heart and Diabetes Institute;
- 2 Department of Medicine, Vanderbilt University School of Medicine, Nashville;
- 3 Monash University;
- 4 Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York;
- 5 Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
- 6 Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn
- ↵* Corresponding author; email: annas.al-sharea{at}baker.edu.au
Abstract
Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease 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, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation 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 endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.
- Received March 7, 2018.
- Accepted October 22, 2018.
- Copyright © 2018, Ferrata Storti Foundation