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

Background: Aging is associated with adipose tissue alterations, oxidative stress, and fibrosis together with the onset of cardiometabolic complications such as atherosclerosis. Although it has been shown that perivascular adipose tissue (PVAT) can participate to vascular damage, the involvement of subcutaneous adipose tissue (SCAT) - particularly through its secretory activity - in vascular aging remains poorly understood. We have previously shown 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 in vascular aging. Methods: Conditioned media were prepared from ASCs isolated from SCAT of healthy young (<25y) or aged (>60y) women. The secretome of ASCs was analysed and added on human coronary artery endothelial cells (HCAEC). 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 characterized by lower nitric oxide production, higher oxidative stress, senescence (greater p16 expression), and a pro-adherent phenotype (elevated adhesion molecule secretion). Aged-donor ASCs also favored the Endothelial-to-mesenchymal transition, characterised by the higher expression of mesenchymal markers and a pro-migratory profile. We showed that CCL5/RANTES was secreted at a higher level 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. Moreover, we showed both in HCAEC and in a human cohort that the CCL5/RANTES receptor antagonist drug maraviroc prevented the deleterious impact of CCL5/RANTES. 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 - and a potential link between these phenomena and hypertension in particular.