Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness

BACKGROUND: 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. METHODS AND RESULTS: 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 Ccr2 knock-in ( Ccr2 gfp )/knock-out ( Ccr2 KO ) mice, we observed that Ang II–mediated increases in Ccr2 + macrophages were expressed in Ccr2 gfp mice but were absent in Ccr2 KO mice. Also, Ang II–induced increases in synapsin expression, neighboring Ccr2 + cells, AA thickness, and pulse wave velocity were reduced in Ccr2 KO mice. Both Ki20227 and Ccr2 KO 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. CONCLUSIONS: Exercise mitigates Ang II–mediated sympathetic axon interaction with the circulating monocyte-derived macrophages in the AA to attenuate vascular fibrosis and aortic stiffness.