Journal article
Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness
Circulation research, Vol.136(12), pp.1579-1594
06/06/2025
DOI: 10.1161/CIRCRESAHA.124.325656
PMCID: PMC12140871
PMID: 40304034
Abstract
Exercise augments hemodynamic shear to activate mechano-sensitive molecular transducers in the vascular endothelium. Recently, the central nervous system has been reported to mediate neuroimmune interaction in the aortic adventitia (AA). Whether exercise modulates the sympathetic nerve interaction with the immune cells to mitigate aortic stiffness remains unknown.
Four weeks of Ang II (angiotensin II) infusion to C57BL/6 mice increased neural activation to increase the expression of TH (tyrosine hydroxylase) for sympathetic nerve axons and norepinephrine levels along with the colocalization of synapsin and β2-AR (β2-adrenergic receptor)-positive macrophages in the AA. This Ang II-mediated sympathetic nerve and macrophage interaction activated fibroblasts to increase vascular fibrosis and arterial pulse wave velocity. Sympathetic denervation with celiac ganglionectomy or 6-hydroxydopamine treatment abrogated Ang II-mediated TH
, AA thickness, and pulse wave velocity. Single-cell RNA sequencing analyses of the AA revealed that Ang II increased the circulating monocyte-derived macrophages (Ccr2
CD80) but reduced the resident macrophages (Lyve1
CD163). Gene ontology analysis of differentially expressed genes unveiled that voluntary wheel running mitigated Ang II-mediated increase in Ccr2
CD80 macrophages, cytokine-mediated signaling pathways in macrophages, and extracellular matrix deposition in fibroblasts. Macrophage depletion with Ki20227 (colony stimulating factor 1 receptor inhibitor) reduced Ang II-mediated synapsin
macrophages. Using the
knock-in (
)/knock-out (
) mice, we observed that Ang II-mediated increases in
macrophages were expressed in
mice but were absent in
mice. Also, Ang II-induced increases in synapsin expression, neighboring
cells, AA thickness, and pulse wave velocity were reduced in
mice. Both Ki20227 and
reduced the Ang II-mediated increase in TH levels. Furthermore, voluntary wheel running-mediated reduction in vascular fibrosis and aortic stiffness were mitigated by a β2-AR agonist, terbutaline, indicating β2-AR in neuroimmune modulation.
Exercise mitigates Ang II-mediated sympathetic axon interaction with the circulating monocyte-derived macrophages in the AA to attenuate vascular fibrosis and aortic stiffness.
Details
- Title: Subtitle
- Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness
- Creators
- Jae Min Cho - David Geffen School of Medicine at UCLAKhoa Vu - University of California, Los AngelesSeul-Ki Park - David Geffen School of Medicine at UCLAEnbo Zhu - David Geffen School of Medicine at UCLAYan-Ruide Li - University of California, Los AngelesPeng Zhao - David Geffen School of Medicine at UCLATomohiro Yokota - David Geffen School of Medicine at UCLALili Yang - UCLA Jonsson Comprehensive Cancer CenterRong Lu - Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles (R.L.)Yang Kevin Xiang - VA Northern California Healthcare System, Mather, CA (Y.K.X.)Ying H Shen - Baylor College of MedicineMark W Chapleau - Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine (M.W.C.)Tzung K Hsiai - Medical Engineering, California Institute of Technology, Pasadena, CA (T.K.H.)
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.136(12), pp.1579-1594
- DOI
- 10.1161/CIRCRESAHA.124.325656
- PMID
- 40304034
- PMCID
- PMC12140871
- NLM abbreviation
- Circ Res
- ISSN
- 1524-4571
- eISSN
- 1524-4571
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Grant note
- American Heart Association (AHA): R01 HL159970, T32 HL144449, 946220, I01 BX004356, I01BX007201
Supported by R01 HL159970 (T.K. Hsiai), T32 HL144449 (E. Zhu and J.M. Cho), American Heart Association (AHA) 946220 (T.K. Hsiai), I01 BX004356 (T.K. Hsiai), and I01BX007201 (T.K. Hsiai).
- Language
- English
- Electronic publication date
- 04/30/2025
- Date published
- 06/06/2025
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984816017702771
Metrics
12 Record Views