Aging reduces susceptibility of vascular smooth muscle cells to H2O2-induced apoptosis through the down-regulation of Jagged1 expression in endothelial cells

Abstract

In addition to excessive proliferation, reduced apoptosis of vascular smooth muscle cells (VSMCs) plays a key role in aging-exaggerated neointima formation after vascular injury. Our previous studies have shown that impaired expression of Jagged1 in the endothelium may be a key event that leads to enhanced VSMC proliferation in the elderly. Here, we are the first to investigate whether the expression of Jagged1 in endothelial cells (ECs) may regulate apoptosis of VSMCs. We discovered that VSMCs co-cultured with senescent ECs exhibited decreased susceptibility to H₂O₂-induced apoptosis compared with those co-cultured with young ECs. Senescent ECs also displayed lower Jagged1 expression compared to young ECs, which was more evident after H₂O₂ stimulation. Overexpression of Jagged1 in senescent ECs significantly promoted H₂O₂-induced apoptosis in the co-cultured VSMCs, whereas silencing Jagged1 expression in young ECs reduced H2O2-induced apoptosis in the co-cultured VSMCs. Our studies also revealed that Jagged1 expressed in ECs exerted its pro-apoptotic activity by lowering expression of the anti-apoptotic protein Bcl-2. These results demonstrate that aging reduces the susceptibility of co-cultured VSMCs to H₂O₂-induced apoptosis through impaired Jagged1 expression in ECs.