CCL5 signaling is associated with impaired vascular function with age

• Published in: Physiology (Bethesda, Md.) Md.), 2023-05, Vol.38 (S1)
• Main Authors: Velusamy, Prema, Grotle, Ann-Katrin, Skow, Rachel, Fadel, Paul, Trott, Daniel
• Format: Article
• Language: English
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5733402

Abstract only Aging is the most important and predictable risk factor for cardiovascular diseases, the major hallmarks of which are hypertension, arterial stiffness and impaired endothelial function. CCL5, a chemokine also called RANTES (Regulated upon Activation, Normal T-cell Expressed and Presumably Secreted) is expressed in T-cells and monocytes. Immune cells have been implicated in arterial inflammation and dysfunction with advancing age. More importantly T-cell activation has been known to contribute to endothelial dysfunction and large artery stiffness in rodent models of acute hypertension. In these rodent studies CCL5 mediates T-cell accumulation around the arteries. The T-box transcription factor, Eomes is the master regulator of CD8 effector and memory T-cells and plays a critical role in T-cell immune response. We previously reported that these effector CD8 cells accumulate in the aorta and mesenteric vasculature in older mice. However, whether CCL5 signaling and T-cell Eomes are associated with arterial dysfunction in older humans is unknown. Therefore, we tested the hypothesis that CCL5 signaling is associated with age related declines in vascular function. We measured plasma CCL5 in a cohort of 9 healthy young (age: 27 ± 4 years; 6 males) and 11 older individuals (age: 60 ± 9 years; 3 males). We also measured CCR5 in T-cells isolated from whole blood using flow cytometry in a subset of healthy young (n=3) and older (n=5) subjects. Endothelial function was assessed as brachial artery flow-mediated dilation (FMD; %) using duplex Doppler ultrasound. We observed that plasma CCL5 (Young: 2632.5 ± 318.5, Older: 4191.1 ± 537.87 pg/mL, p=0.0303) was significantly elevated in the aged individuals when compared to young controls. There was a strong negative correlation between plasma CCL5 levels and FMD (R2=0.5446; p=0.0040). From the flow cytometry data, we found that CD8 cells from older adults exhibited greater Eomes protein content compared to young controls (young: 2699 ± 488.08, older: 14616 ± 5104.17 MFI, p=0.0198). A large proportion of Eomeshi cells were also CCR5 positive (young: 28.65 ± 2.16, older: 46.5 ± 8.83 %, p=0.0357), suggesting that in addition to memory differentiation, Eomes may play a role in CCL5 signaling with age. These preliminary results provide evidence that CCL5 signaling, which mediates T-cell recruitment to the artery with age in animal models, is also upregulated in older adults and associated with reduced endothelial f