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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)129-39
Number of pages11
JournalCardiovascular Research
Volume110
Issue number1
DOIs
Publication statusPublished - 2016

Cite this

Haasdijk, R. A., Den Dekker, W. K., Cheng, C., Tempel, D., Szulcek, R., Bos, F. L., ... Duckers, H. J. (2016). THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice. Cardiovascular Research, 110(1), 129-39. https://doi.org/10.1093/cvr/cvw015
Haasdijk, Remco A ; Den Dekker, Wijnand K ; Cheng, Caroline ; Tempel, Dennie ; Szulcek, Robert ; Bos, Frank L ; Hermkens, Dorien M A ; Chrifi, Ihsan ; Brandt, Maarten M ; Van Dijk, Chris ; Xu, Yan Juan ; Van De Kamp, Esther H M ; Blonden, Lau A J ; Van Bezu, Jan ; Sluimer, Judith C ; Biessen, Erik A L ; Van Nieuw Amerongen, Geerten P ; Duckers, Henricus J. / THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice. In: Cardiovascular Research. 2016 ; Vol. 110, No. 1. pp. 129-39.
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title = "THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice",
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.",
keywords = "Animals, Apolipoproteins E, Atherosclerosis, Carotid Artery Diseases, Endothelial Cells, Female, Humans, Male, Mice, Inbred C57BL, Microvessels, Neovascularization, Pathologic, Phosphatidylinositol 3-Kinases, Plaque, Atherosclerotic, Thrombospondin 1, Thrombospondins, Journal Article, Research Support, Non-U.S. Gov't",
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 {Van Nieuw Amerongen}, {Geerten P} and Duckers, {Henricus J}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\circledC} The Author 2016. For permissions please email: journals.permissions@oup.com.",
year = "2016",
doi = "10.1093/cvr/cvw015",
language = "English",
volume = "110",
pages = "129--39",
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, Van Nieuw Amerongen, GP & Duckers, HJ 2016, 'THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice' Cardiovascular Research, vol. 110, no. 1, pp. 129-39. https://doi.org/10.1093/cvr/cvw015

THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice. / Haasdijk, Remco A; Den Dekker, Wijnand K; Cheng, Caroline; Tempel, Dennie; Szulcek, Robert; Bos, Frank L; Hermkens, Dorien M A; Chrifi, Ihsan; Brandt, Maarten M; Van Dijk, Chris; Xu, Yan Juan; Van De Kamp, Esther H M; Blonden, Lau A J; Van Bezu, Jan; Sluimer, Judith C; Biessen, Erik A L; Van Nieuw Amerongen, Geerten P; Duckers, Henricus J.

In: Cardiovascular Research, Vol. 110, No. 1, 2016, p. 129-39.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

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 - Van Nieuw Amerongen, Geerten P

AU - Duckers, Henricus J

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Animals

KW - Apolipoproteins E

KW - Atherosclerosis

KW - Carotid Artery Diseases

KW - Endothelial Cells

KW - Female

KW - Humans

KW - Male

KW - Mice, Inbred C57BL

KW - Microvessels

KW - Neovascularization, Pathologic

KW - Phosphatidylinositol 3-Kinases

KW - Plaque, Atherosclerotic

KW - Thrombospondin 1

KW - Thrombospondins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/cvr/cvw015

DO - 10.1093/cvr/cvw015

M3 - Article

VL - 110

SP - 129

EP - 139

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -