Endothelial cell-derived pro-fibrotic factors increase TGF-β1 expression by smooth muscle cells in response to cycles of hypoxia-hyperoxia.
Endothelial cell-derived pro-fibrotic factors increase TGF-β1 expression by smooth muscle cells in response to cycles of hypoxia-hyperoxia.
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DOI：
10.1016/j.bbadis.2021.166278
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发表时间：
2022-01-01
期刊：
影响因子：
--
通讯作者：
Koutakis P
中科院分区：
文献类型：
--
作者：
Ismaeel A;Miserlis D;Papoutsi E;Haynatzki G;Bohannon WT;Smith RS;Eidson JL;Casale GP;Pipinos II;Koutakis P
外周动脉疾病（PAD）的血管病理学包括响应于缺血-再灌注（I/R）周期的异常微血管结构和纤维化。我们的目的是研究在I/R的情况下，微血管的病理变化直接纤维化的机制。原代培养的人主动脉内皮细胞（EC）在常氧-缺氧（NH）或常氧-缺氧-高氧（NHH）循环下模拟I/R。培养原代人主动脉平滑肌细胞（SMC），并用来自EC的培养基处理。促纤维化因子血小板衍生生长因子（PDGF）-BB和结缔组织生长因子（CTGF）的mRNA和蛋白表达在经历NH或NHH周期的EC中显著上调。用来自经历NH或NHH循环的EC的培养基处理SMC导致TGF-β1、TGF-β途径信号传导中间体和胶原蛋白表达显著增加。在培养基中加入抗PDGF-BB和CTGF的中和抗体可减弱TGF-β1和胶原表达的增加。用PAD患者来源的血清处理SMC也导致TGF-β1水平增加。在体外I/R模型中，其概括了PAD的病理生理学，显示EC分泌的PDGF-BB和CTGF的增加主要驱动SMC的TGF-β1介导的表达。这些细胞培养实验有助于阐明I/R相关微血管纤维化中EC和SMC之间的机制和相互作用。因此，靶向这些促纤维化因子可能是对抗I/R周期引起的纤维化的有效策略。美国国立卫生研究院国家老龄化研究所批准号R 01 AG 064420。
The vascular pathology of peripheral artery disease (PAD) encompasses abnormal microvascular architecture and fibrosis in response to ischemia-reperfusion (I/R) cycles. We aimed to investigate the mechanisms by which pathological changes in the microvasculature direct fibrosis in the context of I/R. Primary human aortic endothelial cells (ECs) were cultured under cycles of normoxia-hypoxia (NH) or normoxia-hypoxia-hyperoxia (NHH) to mimic I/R. Primary human aortic smooth muscle cells (SMCs) were cultured and treated with media from the ECs. The mRNA and protein expression of the pro-fibrotic factors platelet derived growth factor (PDGF)-BB and connective tissue growth factor (CTGF) were significantly upregulated in ECs undergoing NH or NHH cycles. Treatment of SMCs with media from ECs undergoing NH or NHH cycles led to significant increases in TGF-β1, TGF-β pathway signaling intermediates, and collagen expression. Addition of neutralizing antibodies against PDGF-BB and CTGF to the media blunted the increases in TGF-β1 and collagen expression. Treatment of SMCs with PAD patient-derived serum also led to increased TGF-β1 levels. In an in-vitro model of I/R, which recapitulates the pathophysiology of PAD, increased secretion of PDGF-BB and CTGF by ECs was shown to be predominantly driving TGF-β1-mediated expression by SMCs. These cell culture experiments help elucidate the mechanism and interaction between ECs and SMCs in microvascular fibrosis associated with I/R. Thus, targeting these pro-fibrotic factors may be an effective strategy to combat fibrosis in response to cycles of I/R. National Institute on Aging at the National Institutes of Health grant number R01AG064420.
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外周动脉疾病中的氧化应激和动脉功能障碍。
DOI：
10.3390/antiox7100145
发表时间：
2018-10-19
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ismaeel A;Brumberg RS;Kirk JS;Papoutsi E;Farmer PJ;Bohannon WT;Smith RS;Eidson JL;Sawicki I;Koutakis P
通讯作者：
Koutakis P
影响因子：
3.4
作者：
Ge X;Chen SY;Liu M;Liang TM;Liu C
通讯作者：
Liu C
DOI：
10.1083/jcb.114.6.1285
发表时间：
1991-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bradham DM;Igarashi A;Potter RL;Grotendorst GR
通讯作者：
Grotendorst GR
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
4.3
作者：
Dardik, A;Yamashita, A;Sumpio, BE
通讯作者：
Sumpio, BE