THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice

被引：32

作者：

Haasdijk, Remco A. ^{[1
]}

Den Dekker, Wijnand K. ^{[1
]}

Cheng, Caroline ^{[1
,2
]}

Tempel, Dennie ^{[3
]}

Szulcek, Robert ^{[4
]}

Bos, Frank L. ^{[1
,5
]}

Hermkens, Dorien M. A. ^{[1
,5
]}

Chrifi, Ihsan ^{[1
,2
]}

Brandt, Maarten M. ^{[1
,2
]}

Van Dijk, Chris ^{[2
]}

Xu, Yan Juan ^{[2
]}

Van De Kamp, Esther H. M. ^{[1
]}

Blonden, Lau A. J. ^{[1
]}

Van Bezu, Jan ^{[4
]}

Sluimer, Judith C. ^{[6
]}

Biessen, Erik A. L. ^{[6
]}

Amerongen, Geerten P. Van Nieuw ^{[4
]}

Duckers, Henricus J. ^{[3
]}

机构：

[1] Erasmus MC, Dept Cardiol, Rotterdam, Netherlands

[2] Univ Med Ctr Utrecht, Dept Hypertens & Nephrol, Div Internal Med & Dermatol, Regenerat Vasc Med Lab, Heidelberglaan 100,POB 85500, NL-3508 GA Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Dept Cardiol, Heidelberglaan 100,POB 85500, NL-3508 GA Utrecht, Netherlands

[4] Vrije Univ Amsterdam, Med Ctr Amsterdam, Inst Cardiovasc Res, Dept Physiol, Amsterdam, Netherlands

[5] Hubrecht Inst, Utrecht, Netherlands

[6] Maastricht Univ, Med Ctr, Dept Pathol, NL-6200 MD Maastricht, Netherlands

来源：

CARDIOVASCULAR RESEARCH | 2016年 / 110卷 / 01期

关键词：

Vulnerable plaque; Intraplaque haemorrhage; Endothelial function; THSD1; ENDOTHELIAL ADHERENS JUNCTIONS; VE-CADHERIN; PERMEABILITY; PLAQUE; ATHEROSCLEROSIS; INTERLEUKIN-10; STABILIZATION; ANGIOGENESIS; PROGRESSION; PATHWAY;

D O I：

10.1093/cvr/cvw015

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease. Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-atherogenic factors (3% O-2 and TNF alpha) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly. THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.

引用

页码：129 / 139

页数：11

共 29 条

[1] Cdc42 regulates the restoration of endothelial adherens junctions and permeability [J].