C-C chemokine ligand 5 from women subcutaneous adipose tissue has a central role in vascular aging

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BACKGROUND: Aging is associated with adipose tissue alterations, oxidative stress, and fibrosis and the onset of cardiometabolic complications. While it has been shown that perivascular adipose tissue (PVAT) contributes to vascular damage, the involvement of subcutaneous adipose tissue (SCAT) - particularly through its secretory activity - in vascular aging remains poorly understood. Previously, we have demonstrated that human adipose-derived stromal cells (ASCs) from the SCAT of aged women display senescence and oxidative stress. We hypothesized that the ASC secretome contributes to the onset of endothelial dysfunction, an early stage of vascular aging. METHODS: We prepared conditioned media from ASCs isolated from SCAT of healthy young (< 25y) or aged (> 60y) women. The ASCs secretome was analyzed and added on human coronary artery endothelial cells (HCAECs). Using clinical cohorts, we evaluated the expression of C-C-chemokine-ligand-5 (CCL5)/Regulated upon-Activation-Normally-T-expressed-and-secreted (RANTES) in adipose tissue of individuals with coronary heart disease. RESULTS: The secretome of aged-donor ASCs induced endothelial cell dysfunction in HCAEC, as evidenced by lower nitric oxide production, higher oxidative stress, senescence, and a pro-adherent phenotype. Aged-donor ASCs also favored the endothelial-to-mesenchymal transition, characterized by the higher expression of mesenchymal markers, a pro-migratory profile and angiogenesis. We showed that the higher secretion of CCL5/RANTES in the secretome of aged- vs. young-donor ASCs and was responsible for these effects. Accordingly, CCL5/RANTES expression in SCAT, but not in epicardial adipose tissue, was associated with blood pressure in patients with coronary heart diseases, thus confirming the important role of SCAT in the onset of cardiometabolic disorders. CCL5’s ability to induce endothelial cell dysfunction and senescence was confirmed using a recombinant CCL5 and a CCL5/RANTES neutralizing antibody. Furthermore, we demonstrated that the CCL5/RANTES receptor antagonist drug maraviroc prevented the deleterious impact of CCL5/RANTES in both HCAECs and human cohorts. Thus, CCL5/RANTES secreted from SCAT during aging could contribute to endothelial dysfunction by exerting both local and systemic effects. CONCLUSIONS: Our results highlighted the ability of the CCL5/RANTES released from aging SCAT and, specifically, from adipose stromal cells, to induce endothelial dysfunction and senescence - both of which are early steps in vascular aging - as well as a potential link between these phenomena and hypertension in particular.

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