Abstract
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.
Highlights
Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and damage or death of VSMCs contributes to multiple vascular pathologies
To determine the soluble cytokines released during VSMC apoptosis, we examined conditioned media of apoptotic cells and the adjacent live cells by multiplex cytokine array, and quantified relative concentrations of specific cytokines by ELISA
To determine whether synthesis of these cytokines was increased by apoptosis, or apoptosis just caused release from preformed stores, VSMCs were incubated with actinomycin D (ActD) prior to induction of apoptosis, and interleukin 6 (IL-6) and GMCSF mRNA assayed by qPCR. α-Fas + CHX and staurosporine markedly increased IL-6 mRNA, while α-Fas + CHX increased granulocyte-macrophage colony stimulating factor (GM-CSF) compared with control-treated cells
Summary
Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and damage or death of VSMCs contributes to multiple vascular pathologies. Can reduce VSMC number [1], in many cases VSMC apoptosis is accompanied by changes in cell proliferation, cell migration, inflammation or further apoptosis, for example in developmental closure of the ductus arteriosus [2], vessel remodeling after changes in blood flow [3,4,5], vein grafting to arteries [6], and after injury [7]. VSMC proliferation after injury has been ascribed to exposure to mitogens released from the circulation (e.g. Platelet-derived growth factor from platelets) or vessel wall (e.g. Fibroblast growth factor). VSMCs in development or after birth appear to proliferate and remodel the artery after apoptosis without exposure to these injuryinduced cytokines. VSMC apoptosis after injury is extensive, and has been ascribed to the injury stimulus; it’s not clear if the dead cells signal to induce apoptosis
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