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

Remco A. Haasdijk; Wijnand K. Den Dekker; Caroline Cheng; Dennie Tempel; Robert Szulcek; Frank L. Bos; Dorien M. A. Hermkens; Ihsan Chrifi; Maarten M. Brandt; Chris Van Dijk; Yan Juan Xu; Esther H. M. Van De Kamp; Lau A. J. Blonden; Jan Van Bezu; Judith C. Sluimer; Erik A. L. Biessen; Geerten P. Van Nieuw Amerongen; Henricus J. Duckers

doi:10.1093/cvr/cvw015

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

Remco A. Haasdijk, Wijnand K. Den Dekker, Caroline Cheng, Dennie Tempel, Robert Szulcek, Frank L. Bos, Dorien M. A. Hermkens, Ihsan Chrifi, Maarten M. Brandt, Chris Van Dijk, Yan Juan Xu, Esther H. M. Van De Kamp, Lau A. J. Blonden, Jan Van Bezu, Judith C. Sluimer, Erik A. L. Biessen, Geerten P. Van Nieuw Amerongen, Henricus J. Duckers^*

^*Corresponding author for this work

Pathologie

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Abstract

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.

Original language	English
Pages (from-to)	129-139
Journal	Cardiovascular Research
Volume	110
Issue number	1
DOIs	https://doi.org/10.1093/cvr/cvw015
Publication status	Published - 1 May 2016

Keywords

Vulnerable plaque
Intraplaque haemorrhage
Endothelial function
THSD1

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10.1093/cvr/cvw015

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Cite this

Haasdijk, R. A., Den Dekker, W. K., Cheng, C., Tempel, D., Szulcek, R., Bos, F. L., Hermkens, D. M. A., Chrifi, I., Brandt, M. M., Van Dijk, C., Xu, Y. J., Van De Kamp, E. H. M., Blonden, L. A. J., Van Bezu, J., Sluimer, J. C., Biessen, E. A. L., Amerongen, G. P. V. N., & Duckers, H. J. (2016). THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE(-/-) mice. Cardiovascular Research, 110(1), 129-139. https://doi.org/10.1093/cvr/cvw015

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title = "THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE(-/-) mice",

abstract = "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.",

keywords = "Vulnerable plaque, Intraplaque haemorrhage, Endothelial function, THSD1",

author = "Haasdijk, {Remco A.} and {Den Dekker}, {Wijnand K.} and Caroline Cheng and Dennie Tempel and Robert Szulcek and Bos, {Frank L.} and Hermkens, {Dorien M. A.} and Ihsan Chrifi and Brandt, {Maarten M.} and {Van Dijk}, Chris and Xu, {Yan Juan} and {Van De Kamp}, {Esther H. M.} and Blonden, {Lau A. J.} and {Van Bezu}, Jan and Sluimer, {Judith C.} and Biessen, {Erik A. L.} and Amerongen, {Geerten P. Van Nieuw} and Duckers, {Henricus J.}",

year = "2016",

month = may,

day = "1",

doi = "10.1093/cvr/cvw015",

language = "English",

volume = "110",

pages = "129--139",

journal = "Cardiovascular Research",

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Haasdijk, RA, Den Dekker, WK, Cheng, C, Tempel, D, Szulcek, R, Bos, FL, Hermkens, DMA, Chrifi, I, Brandt, MM, Van Dijk, C, Xu, YJ, Van De Kamp, EHM, Blonden, LAJ, Van Bezu, J, Sluimer, JC , Biessen, EAL, Amerongen, GPVN & Duckers, HJ 2016, 'THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE(-/-) mice', Cardiovascular Research, vol. 110, no. 1, pp. 129-139. https://doi.org/10.1093/cvr/cvw015

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T1 - THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE(-/-) mice

AU - Haasdijk, Remco A.

AU - Den Dekker, Wijnand K.

AU - Cheng, Caroline

AU - Tempel, Dennie

AU - Szulcek, Robert

AU - Bos, Frank L.

AU - Hermkens, Dorien M. A.

AU - Chrifi, Ihsan

AU - Brandt, Maarten M.

AU - Van Dijk, Chris

AU - Xu, Yan Juan

AU - Van De Kamp, Esther H. M.

AU - Blonden, Lau A. J.

AU - Van Bezu, Jan

AU - Sluimer, Judith C.

AU - Biessen, Erik A. L.

AU - Amerongen, Geerten P. Van Nieuw

AU - Duckers, Henricus J.

PY - 2016/5/1

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N2 - 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.

AB - 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.

KW - Vulnerable plaque

KW - Intraplaque haemorrhage

KW - Endothelial function

KW - THSD1

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DO - 10.1093/cvr/cvw015

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JO - Cardiovascular Research

JF - Cardiovascular Research

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