Exercise Modulates Neuro-Immune-Vascular Interaction to Mitigate Arterial Fibrosis

About This Grant

Abstract Cardiometabolic diseases (CMDs), including obesity, have reached epidemic proportions, affecting > 70% of the US adults and > 50% of persons worldwide. Exercise training is cost-effective to mitigate the modifiable CMD risk factors for our veterans. During the previous funding cycle, we demonstrated that habitual exercise activates hemodynamic shear-responsive molecular transducers to catalyze the anti-inflammatory metabolites in vascular endothelium. However, exercise training also modulates parasympathetic and sympathetic outflow to ameliorate vascular dysfunction and arterial stiffness. Recently, interaction between autonomic nervous system and immune cells was a reported to promote the lymphoid organs to mediate atherosclerosis in the aortic adventitia. Over the past decades, we and others have primarily focused on the vascular endothelium and smooth muscle cells in vascular remodeling. Specifically, shear stress-responsive endothelial nitric oxide synthase (eNOS) is well-known to catalyze nitric oxide production and its metabolites (NO⋅  NO2- + NO3-),9 and oxidative stress induces vascular smooth muscle cells to undergo the transformation from the contractile to fibrotic phenotypes. However, in the aortic adventitia, extracellular matrix (ECM) deposition has been observed in the Angiotensin II (Ang II)-infused hypertensive mice, and immune cells; namely T cells, were identified to prime perivascular fibrosis. While Ang II activates sympathetic nervous system, the mechanism whereby exercise reduces neuro-immune cell interaction to mitigate Ang II-mediated aortic inflammation and vascular fibrosis remains unknown. In this context, we hypothesize that habitual exercise mitigates Ang II-mediated neuro-immune interaction to reduce inflammatory macrophages and activation of fibroblasts. Our hypothesis is supported by our preliminary findings: 1) Ang II-induced sympathetic nerve axons and norepinephrine release to activate the β2-adrenergic receptor (β2-AR)-positive macrophages; 2) Ang II increases monocytes in the bone marrow (BM) and monocyte-derived macrophages; and 3) four weeks of voluntary wheel running (VWR) mitigates Ang II-mediated vascular fibrosis, pulse wave velocity (a surrogate for arterial stiffness), and blood pressure. To test our hypothesis, we have three aims: In Aim 1, we plan to elucidate Ang II-mediated sympathetic nerve-macrophage interaction. In Aim 2, we plan to Investigate Ang II-mediated Ccr2+macrophages to activate fibroblasts. In Aim 3, we plan to demonstrate exercise-mitigated sympathetic and macrophage interaction to reduce vascular fibrosis. We will determine the role of the β2-AR using macrophage- specific β2-AR KO mice and investigate macrophage-fibroblast communication. We will profile BM hematopoietic stem cells and progenitors, and perform BM transplantation to elucidate exercise-mitigated β2- AR+ macrophage. Overall, elucidating exercise-mitigated neuroimmune interaction paves the way for identifying therapeutic targets to modify cardiometabolic disorders for our war fighters, veterans, and their families.