Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts.
Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts.
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DOI：
10.1016/j.jvs.2011.04.037
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Rade, Jeffrey J.
中科院分区：
文献类型：
--
作者：
Kapur, Navin K.;Bian, Ce;Lin, Edward;Deming, Clayton B.;Sperry, Jason L.;Hansen, Baranda S.;Kakouros, Nikolaos;Rade, Jeffrey J.
Thrombosis is a major cause of the early failure of vein grafts (VGs) implanted during peripheral and coronary arterial bypass surgeries. Endothelial expression of thrombomodulin (TM), a key constituent of the protein C anticoagulant pathway, is markedly suppressed in VG after implantation and contributes to local thrombus formation. While stretch-induced paracrine release of transforming growth factor-β (TGF-β) is known to negatively regulate TM expression in heart tissue, its role in regulating TM expression in VGs remains unknown. Changes in relative mRNA expression of major TGF-β isoforms were measured by qPCR in cultured human saphenous vein smooth muscle cells (HSVSMC) subjected to cyclic stretch. To determine the effects of paracrine release of TGF-β on endothelial TM mRNA expression, human saphenous vein endothelial cells (HSVEC) were co-cultured with stretched HSVSMC in the presence of 1D11, a pan-neutralizing TGF-β antibody, or 13C4, an isotype-control antibody. Groups of rabbits were then administered 1D11 or 13C4 and underwent interpositional grafting of jugular vein segments into the carotid circulation. The effect of TGF-β inhibition on TM gene expression was measured by qPCR, protein C activating capacity and local thrombus formation were measured by in situ chromogenic substrate assays, and VG remodeling was assessed by digital morphometry. Cyclic stretch induced TGF-β1 expression in HSVSMC by 1.9±0.2-fold, P<.001 without significant chang in the expressions of TGF-β2 and TGF-β3. Paracrine release of TGF-β1 by stretched HSVSMC inhibited TM expression in stationary HSVEC placed in co-culture by 57±12%, P=.03, an effect that was abolished in the presence of 1D11. Similarly, TGF-β1 was the predominant isoform induced in rabbit VGs 7 days after implantation (3.5±0.4-fold induction, P<.001). TGF-β1 protein expression localized predominantly to the developing neointima and coincided with marked suppression of endothelial TM expression (16±2% of vein controls, P<.03), a reduction in situ APC-generating capacity (53±9% of vein controls, P=.001) and increased local thrombus formation (3.7±0.8-fold increase over vein controls, P<.01). External stenting of VGs to limit vessel distension significantly reduced TGF-β1 induction and TM downregulation. Systemic administration of 1D11 also effectively prevented TM downregulation, preserved activated protein C-generating capacity and reduced local thrombus in rabbit VGs without observable effect on neointima formation and other morphometric parameters 6 weeks after implantation. TM downregulation in VGs is mediated by paracrine release of TGF-β1 caused by pressure-induced vessel stretch. Systemic administration of an anti-TGF-β antibody effectively prevented TM downregulation and preserved local thromboresistance without negative effect on VG remodeling.
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DOI：
10.1161/01.atv.12.2.135
发表时间：
1992-02-01
期刊：
ARTERIOSCLEROSIS AND THROMBOSIS
影响因子：
--
作者：
ESMON, CT
通讯作者：
ESMON, CT
DOI：
10.1152/ajpheart.00268.2009
发表时间：
2009-10-01
影响因子：
4.8
作者：
Jiang, Zhihua;Tao, Ming;Berceli, Scott A.
通讯作者：
Berceli, Scott A.
影响因子：
4.8
作者：
Sandusky, G;Berg, DT;Grinnell, BW
通讯作者：
Grinnell, BW
影响因子：
20.1
作者：
Sperry, JL;Deming, CB;Rade, JJ
通讯作者：
Rade, JJ
影响因子：
20.1
作者：
Kim, AY;Walinsky, PL;Rade, JJ
通讯作者：
Rade, JJ