Cytokine regulation of apoptosis-induced apoptosis and apoptosis-induced cell proliferation in vascular smooth muscle ce
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Cytokine regulation of apoptosis-induced apoptosis and apoptosisinduced cell proliferation in vascular smooth muscle cells Dimitra Aravani1 · Kirsty Foote1 · Nichola Figg1 · Alison Finigan1 · Anna Uryga1 · Murray Clarke1 · Martin Bennett1
© The Author(s) 2020
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 proapoptotic stimuli in vessel remodeling and disease. Keywords Apoptosis · Proliferation · Vascular smooth muscle · Cytokine
Introduction Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and damage or death of VSMCs contributes to multiple vascular pathologies. In particular, apoptosis of VSMCs has been described in atherosclerosis (which underlies most heart attacks and strokes), arterial aneurysm, after injury (e.g. percutaneous coronary intervention) and in development. Although chronic apoptosis Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01622-4) contains supplementary material, which is available to authorized users. * Martin Bennett [email protected] 1
Division of Cardiovascular Medicine, University of Cambridge, ACCI, Addenbrooke’s Hospital, Box 110, CB2 0QQ Cambridge, UK
can reduce VSMC number [1], in many cases VSMC apoptosis is accompanied by changes in cell proliferation, cell migrat
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