1. THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice.
- Author
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Haasdijk RA, Den Dekker WK, Cheng C, Tempel D, Szulcek R, Bos FL, Hermkens DM, Chrifi I, Brandt MM, Van Dijk C, Xu YJ, Van De Kamp EH, Blonden LA, Van Bezu J, Sluimer JC, Biessen EA, Van Nieuw Amerongen GP, and Duckers HJ
- Subjects
- Animals, Apolipoproteins E deficiency, Apolipoproteins E metabolism, Carotid Artery Diseases metabolism, Female, Humans, Male, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases metabolism, Plaque, Atherosclerotic pathology, Thrombospondin 1 metabolism, Atherosclerosis metabolism, Endothelial Cells metabolism, Microvessels metabolism, Neovascularization, Pathologic metabolism, Thrombospondins metabolism
- Abstract
Aims: 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., Methods and Results: 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% O2 and TNFα) 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., Conclusion: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)
- Published
- 2016
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