Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and VSMC apoptosis occurs in vascular disease, after injury, and in vessel remodeling during development. Although VSMC apoptosis is viewed as silent, recent studies show that apoptotic cells can promote apoptosis-induced compensatory proliferation (AICP), apoptosis-induced apoptosis (AIA), and migration of both local somatic and infiltrating inflammatory cells. However, the effects of VSMC apoptosis on adjacent VSMCs, and their underlying signaling and mechanisms are unknown. We examined the consequences of VSMC apoptosis after activating extrinsic and intrinsic death pathways. VSMCs undergoing apoptosis through Fas/CD95 or the protein kinase inhibitor staurosporine transcriptionally activated interleukin 6 (IL-6) and granulocyte-macrophage colony stimulating factor (GM-CSF), leading to their secretion. Apoptosis induced activation of p38MAPK, JNK, and Akt, but neither p38 and JNK activation nor IL-6 or GM-CSF induction required caspase cleavage. IL-6 induction depended upon p38 activity, while Fas-induced GM-CSF expression required p38 and JNK. Conditioned media from apoptotic VSMCs induced VSMC apoptosis in vitro, and IL-6 and GM-CSF acted as pro-survival factors for AIA. VSMC apoptosis was studied in vivo using SM22α-DTR mice that express the diphtheria toxin receptor in VSMCs only. DT administration induced VSMC apoptosis and VSMC proliferation, and also signficantly induced IL-6 and GM-CSF. We conclude that VSMC apoptosis activates multiple caspase-independent intracellular signaling cascades, leading to release of soluble cytokines involved in regulation of both cell proliferation and apoptosis. VSMC AICP may ameliorate while AIA may amplify the effects of pro-apoptotic stimuli in vessel remodeling and disease.

血管平滑肌细胞（VSMC）是血管的主要结构细胞，VSMC凋亡发生在血管疾病、损伤后以及发育过程中的血管重塑中。尽管VSMC凋亡被认为是沉默的，但最近的研究表明，凋亡细胞可以促进凋亡诱导的代偿性增殖（AICP）、凋亡诱导的凋亡（AIA）以及局部体细胞和浸润炎症细胞的迁移。然而，VSMC凋亡对邻近VSMC的影响及其潜在的信号传导和机制尚不清楚。我们研究了激活外在和内在死亡途径后 VSMC 凋亡的后果。VSMC 通过 Fas/CD95 或蛋白激酶抑制剂十字孢菌素转录激活白细胞介素 6 (IL-6) 和粒细胞巨噬细胞集落刺激因子 (GM-CSF) 发生凋亡，导致其分泌。细胞凋亡诱导 p38MAPK、JNK 和 Akt 激活，但 p38 和 JNK 激活以及 IL-6 或 GM-CSF 诱导均不需要 caspase 裂解。IL-6 诱导取决于 p38 活性，而 Fas 诱导的 GM-CSF 表达需要 p38 和 JNK。来自凋亡 VSMC 的条件培养基在体外诱导 VSMC 凋亡，IL-6 和 GM-CSF 充当 AIA 的促生存因子。使用仅在 VSMC 中表达白喉毒素受体的 SM22α-DTR 小鼠体内研究了 VSMC 凋亡。DT给药诱导VSMC凋亡和VSMC增殖，并且还显着诱导IL-6和GM-CSF。我们得出结论，VSMC 凋亡激活多个不依赖 caspase 的细胞内信号级联，导致释放参与细胞增殖和凋亡调节的可溶性细胞因子。VSMC AICP 可能会改善，而 AIA 可能会放大促凋亡刺激对血管重塑和疾病的影响。