Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Front Med. 2017 Sep;11(3):403-409. doi: 10.1007/s11684-017-0522-y. Epub 2017 May 27.
Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor-mediated coagulation. TFPI is expressed by endothelial and smooth muscle cells in the vasculature. Endothelium-derived TFPI has been reported to play a regulatory role in arterial thrombosis. However, the role of endogenous TFPI in vascular smooth muscle cells (VSMCs) in thrombosis and vascular disease development has yet to be elucidated. In this TFPI mice crossbred with Sma-Cre mice were utilized to establish TFPI conditional knockout mice and to examine the effects of VSMC-directed TFPI deletion on development, hemostasis, and thrombosis. The mice with deleted TFPI in VSMCs (TFPI) reproduced viable offspring. Plasma TFPI concentration was reduced 7.2% in the TFPI mice compared with TFPI littermate controls. Plasma TFPI concentration was also detected in the TFPI (mice deleted TFPI in endothelial cells and cells of hematopoietic origin) mice. Plasma TFPI concentration of the TFPI mice was 80.4% lower (P < 0.001) than that of the TFPI mice. No difference in hemostatic measures (PT, APTT, and tail bleeding) was observed between TFPI and TFPI mice. However, TFPI mice had increased ferric chloride-induced arterial thrombosis compared with TFPI littermate controls. Taken together, these data indicated that endogenous TFPI from VSMCs inhibited ferric chloride-induced arterial thrombosis without causing hemostatic effects.
组织因子途径抑制剂（TFPI）是组织因子介导的凝血的主要抑制剂。TFPI 由血管中的内皮细胞和平滑肌细胞表达。已报道内皮细胞衍生的 TFPI 在动脉血栓形成中发挥调节作用。然而，内源性 TFPI 在血管平滑肌细胞（VSMCs）中在血栓形成和血管疾病发展中的作用尚未阐明。在这项研究中，将 TFPI 基因敲除小鼠与 Sma-Cre 小鼠杂交，建立 TFPI 条件性敲除小鼠，并研究 VSMC 定向 TFPI 缺失对发育、止血和血栓形成的影响。在 VSMCs 中缺失 TFPI 的小鼠（TFPI）能够繁殖存活的后代。与 TFPI 同窝仔鼠相比，TFPI 小鼠的血浆 TFPI 浓度降低了 7.2%。在 TFPI 小鼠（内皮细胞和造血细胞来源的细胞中缺失 TFPI 的小鼠）中也检测到了血浆 TFPI 浓度。TFPI 小鼠的血浆 TFPI 浓度比 TFPI 小鼠低 80.4%（P<0.001）。TFPI 和 TFPI 小鼠之间的止血措施（PT、APTT 和尾部出血）没有差异。然而，与 TFPI 同窝仔鼠相比，TFPI 小鼠的氯化铁诱导的动脉血栓形成增加。总之，这些数据表明来自 VSMCs 的内源性 TFPI 抑制了氯化铁诱导的动脉血栓形成，而不会引起止血作用。
