TY - JOUR
T1 - Geometric Constraints Regulate Energy Metabolism and Cellular Contractility in Vascular Smooth Muscle Cells by Coordinating Mitochondrial DNA Methylation
AU - Liu, Han
AU - Liu, Yuefeng
AU - Wang, He
AU - Zhao, Qiang
AU - Zhang, Tao
AU - Xie, Si an
AU - Liu, Yueqi
AU - Tang, Yuanjun
AU - Peng, Qin
AU - Pang, Wei
AU - Yao, Weijuan
AU - Zhou, Jing
N1 - Publisher Copyright:
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2022/11/14
Y1 - 2022/11/14
N2 - Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square-shaped geometry causes the nuclear-to-cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3-kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts.
AB - Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square-shaped geometry causes the nuclear-to-cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3-kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts.
KW - DNMT1
KW - cPLA2
KW - geometric constraint
KW - mitochondrial DNA methylation
KW - smooth muscle contractility
UR - http://www.scopus.com/inward/record.url?scp=85137856715&partnerID=8YFLogxK
U2 - 10.1002/advs.202203995
DO - 10.1002/advs.202203995
M3 - Article
AN - SCOPUS:85137856715
SN - 2198-3844
VL - 9
JO - Advanced Science
JF - Advanced Science
IS - 32
M1 - 2203995
ER -