Research Paper Volume 13, Issue 13 pp 16938—16956
Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment
- 1 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 2 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 3 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 4 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 5 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
- 6 Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received: December 11, 2020 Accepted: March 20, 2021 Published: May 17, 2021https://doi.org/10.18632/aging.203054
How to Cite
Copyright: © 2021 Haschak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.