Smooth muscle cells-specific loss of OCT4 accelerates neointima formation after acute vascular injury.
Smooth muscle cells-specific loss of OCT4 accelerates neointima formation after acute vascular injury.
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DOI：
10.3389/fcvm.2023.1276945
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发表时间：
2023
影响因子：
3.6
通讯作者：
Cherepanova, Olga A.
中科院分区：
文献类型：
--
作者：
Shin, Junchul;Tkachenko, Svyatoslav;Gomez, Delphine;Tripathi, Rupande;Owens, Gary K.;Cherepanova, Olga A.
越来越多的证据表明，平滑肌细胞（SMC）表型转变在正常发育和组织恢复过程以及动脉粥样硬化等病理条件中起着关键作用。然而，负责这些转变的分子机制还没有得到很好的理解。最近，我们发现在体细胞中沉默的胚胎干细胞/诱导多能干细胞（iPSC）因子OCT4在SMC中具有动脉粥样硬化保护作用，并通过介导微血管SMC和周细胞迁移来调节角膜碱烧伤和后肢缺血后的血管生成。然而，动脉SMC中OCT4激活的动力学及其在急性病理状态中的作用尚不清楚。在这里，我们使用OCT4 - ires - gfp报告小鼠模型，发现急性结扎性损伤后18小时，颈动脉中的OCT4被重新激活，这是SMC表型转变的常见体内模型。接下来，使用他莫昔芬诱导的Myh11-CreERT2 Oct4敲除小鼠模型，我们发现Oct4的缺失，特别是在SMC中，导致颈动脉结扎后新内膜形成加速和中膜增加，至少部分是通过增加中膜内SMC的增殖。对培养SMC的Bulk RNA测序分析显示，Oct4基因失活后，SMC收缩标记显著下调，属于细胞增殖调控的基因和细胞迁移本体群的正调控基因和负调控基因失调。我们还发现Oct4的缺失导致损伤后和培养的主动脉SMC中收缩性SMC标记物的抑制。进一步的机制研究表明，OCT4调节SMC收缩基因ACTA2和TAGLN，至少部分是通过直接结合这些基因的启动子来实现的。这些结果表明，急性血管损伤后，多能因子OCT4在SMC中快速激活，抑制SMC的过度增殖，可能对防止新生内膜过度形成具有保护作用。
There is growing evidence that smooth muscle cell (SMC) phenotypic transitions play critical roles during normal developmental and tissue recovery processes and in pathological conditions such as atherosclerosis. However, the molecular mechanisms responsible for these transitions are not well understood. Recently, we found that the embryonic stem cell/induced pluripotent stem cell (iPSC) factor OCT4, which was believed to be silenced in somatic cells, plays an atheroprotective role in SMC, and regulates angiogenesis after corneal alkali burn and hindlimb ischemia by mediating microvascular SMC and pericyte migration. However, the kinetics of OCT4 activation in arterial SMC and its role in acute pathological conditions are still unknown. Here, using an Oct4-IRES-GFP reporter mouse model, we found that OCT4 is reactivated in the carotid artery 18 hours post-acute ligation-induced injury, a common in vivo model of the SMC phenotypic transitions. Next, using a tamoxifen-inducible Myh11-CreERT2 Oct4 knockout mouse model, we found that the loss of OCT4, specifically in SMC, led to accelerated neointima formation and increased tunica media following carotid artery ligation, at least in part by increasing SMC proliferation within the media. Bulk RNA sequencing analysis on the cultured SMC revealed significant down-regulation of the SMC contractile markers and dysregulation of the genes belonging to the regulation of cell proliferation and, positive and negative regulation for cell migration ontological groups following genetic inactivation of Oct4. We also found that loss of Oct4 resulted in suppression of contractile SMC markers after the injury and in cultured aortic SMC. Further mechanistic studies revealed that OCT4 regulates SMC contractile genes, ACTA2 and TAGLN, at least in part by direct binding to the promoters of these genes. These results demonstrate that the pluripotency factor OCT4 is quickly activated in SMC after the acute vascular injury and inhibits SMC hyperproliferation, which may be protective in preventing excessive neointima formation.
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影响因子：
82.9
作者：
Gomez D;Baylis RA;Durgin BG;Newman AAC;Alencar GF;Mahan S;St Hilaire C;Müller W;Waisman A;Francis SE;Pinteaux E;Randolph GJ;Gram H;Owens GK
通讯作者：
Owens GK
影响因子：
7.7
作者：
Kehler, J;Tolkunova, E;Tomilin, A
通讯作者：
Tomilin, A
影响因子：
16.6
作者：
Misra A;Feng Z;Chandran RR;Kabir I;Rotllan N;Aryal B;Sheikh AQ;Ding L;Qin L;Fernández-Hernando C;Tellides G;Greif DM
通讯作者：
Greif DM
影响因子：
16.6
作者：
Hess, Daniel L.;Kelly-Goss, Molly R.;Owens, Gary K.
通讯作者：
Owens, Gary K.
DOI：
10.1161/atvbaha.120.314670
发表时间：
2020-09-01
影响因子：
8.7
作者：
Pedroza, Albert J.;Tashima, Yasushi;Fischbein, Michael P.
通讯作者：
Fischbein, Michael P.