Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

doi:10.1007/s11684-017-0522-y

Front. Med.

2017, Vol. 11

Issue (3) : 403-409 https://doi.org/10.1007/s11684-017-0522-y

RESEARCH ARTICLE

Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

Jichun Yang¹, Kaiyue Jin², Jiajun Xiao², Jing Ma², Duan Ma^1,²(

)

¹. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
². 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

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Abstract

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^Flox 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^Sma) reproduced viable offspring. Plasma TFPI concentration was reduced 7.2% in the TFPI^Sma mice compared with TFPI^Flox littermate controls. Plasma TFPI concentration was also detected in the TFPI^Tie2 (mice deleted TFPI in endothelial cells and cells of hematopoietic origin) mice. Plasma TFPI concentration of the TFPI^Tie2 mice was 80.4% lower (P<0.001) than that of the TFPI^Flox mice. No difference in hemostatic measures (PT, APTT, and tail bleeding) was observed between TFPI^Sma and TFPI^Flox mice. However, TFPI^Sma mice had increased ferric chloride–induced arterial thrombosis compared with TFPI^Flox littermate controls. Taken together, these data indicated that endogenous TFPI from VSMCs inhibited ferric chloride–induced arterial thrombosis without causing hemostatic effects.

Keywords arterial thrombosis conditional knockout mice tissue factor pathway inhibitor vascular smooth muscle cells

Corresponding Author(s): Duan Ma

Just Accepted Date: 19 April 2017 Online First Date: 26 May 2017 Issue Date: 29 August 2017

Cite this article:

Jichun Yang,Kaiyue Jin,Jiajun Xiao, et al. Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis[J]. Front. Med., 2017, 11(3): 403-409.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-017-0522-y
https://academic.hep.com.cn/fmd/EN/Y2017/V11/I3/403

Fig.1 Transcriptional efficiency of Cre-mediated deletion. (A) Genotyping of the offspring derived from crossing TFPI^Flox mice with Sma–Cre mice. (B) Relative mRNA levels of TFPI^Sma (n = 3) and TFPI^Flox (n = 3) mice. (C) Immunohistochemical analysis of TFPI expression in TFPI^Sma and TFPI^Flox mice. Representative positive staining areas were pointed by the black arrow.

Fig.2 Plasma TFPI concentration in TFPI^Flox, TFPI^Sma, and TFPI^Tie2 mice. Plasma TFPI concentration was measured in TFPI^Flox (n = 8), TFPI^Sma (n = 11), and TFPI^Tie2 (n = 4) mice using a mouse TFPI ELISA assay. ***P<0.001, compared with TFPI^Flox mice.

Fig.3 Hemostasis in TFPI^Flox and TFPI^Sma mice. (A) Tail bleeding times were determined in TFPI^Flox (n = 18) and TFPI^Sma (n = 21) mice. Horizontal bars represent the median tail bleeding time. (B) Blood loss during the bleeding time experiments was determined by measuring the absorbance at 575 nm of hemoglobin in PBS in which the mouse tails were immersed. Horizontal bars indicated the median absorbance of hemoglobin. (C) PT of TFPI^Flox (n = 7) and TFPI^Sma (n = 5) mice. (D) APTT of TFPI^Flox (n = 7) and TFPI^Sma (n = 5) mice.

Fig.4 VSMC-derived TFPI deficiency promotes FeCl₃-induced carotid artery occlusion. (A) The mouse carotid artery was treated with 10% FeCl₃, as previously described. Traces of blood flow in the carotid arteries of TFPI^Flox and TFPI^Sma mice were presented. (B) The times to occlusion were measured in TFPI^Flox (n = 10) and TFPI^Sma (n = 20) mice (**, P<0.01).

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