Senescent endothelial cell-derived extracellular sulfatase SULF2 contributes to the early stages of atherosclerosis

Endothelial cell (EC) senescence contributes to the onset and progression of vascular diseases, including atherosclerosis. Although senescence-associated secretory phenotype (SASP) factors have been implicated in these processes, the specific factors responsible and their mechanistic roles remain largely undefined. In this study, we found that extracellular sulfatase 2 (SULF2) expression and secretion increase with EC senescence. SULF2 modifies the 6- O -sulfation state of heparan sulfate (HS) chains and regulates cell signaling and the bioavailability of several ligands. We then performed in vitro and in vivo analyses to clarify the functional role of senescent EC-derived SULF2. We demonstrated that autocrine/paracrine SULF2 released from senescent ECs was not involved in senescence-induced endothelial dysfunction, including reduced nitric oxide production, impaired wound healing, and impaired tube formation. We also investigated the role of senescent EC-derived SULF2 in atherosclerosis, a condition associated with senescent ECs. First, in an in vitro experiments relevant to atherosclerosis, we found that 6- O -desulfation of HS by senescent EC-derived SULF2 regulates the presentation of chemotactic factors on senescent ECs, thereby promoting monocyte transendothelial migration. Next, we showed that senescent EC-derived SULF2 was not involved in macrophage differentiation. Finally, we demonstrated, using coculture experiments, that the action of senescent EC-derived SULF2 promoted IFN-β/STAT1 signaling via 6- O -desulfation in macrophages, leading to increased acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) and acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2) expression, which in turn promoted foam cell formation associated with oxidized low-density lipoprotein uptake by macrophages. These in vitro findings suggested that senescent EC-derived SULF2 contributes to atherosclerosis. We then examined the involvement of SULF2 in atherosclerosis in vivo using apolipoprotein E (ApoE)–deficient mice. We found that Sulf2 expression was increased in senescent ECs of ApoE-deficient mice, accompanied by plaque formation during the early stages of atherosclerosis. Furthermore, histological analyses revealed that plaque formation was attenuated in endothelial-specific Sulf2 knockout mice on an ApoE–deficient background. These findings indicate that SULF2, which increases with EC senescence, is involved in the early stages of atherosclerosis. Thus, targeting senescent EC-derived SULF2 may provide a strategy to prevent or attenuate age-associated diseases such as atherosclerosis.