PUBLICATION
THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice
- Authors
- Haasdijk, R.A., den Dekker, W.K., Cheng, C., Tempel, D., Szulcek, R., Bos, F.L., Hermkens, D.M., Chrifi, I., Brandt, M.M., van Dijk, C., Xu, Y.J., van de Kamp, E.H., Blonden, L.A., van Bezu, J., Sluimer, J.C., Biessen, E.A., van Nieuw Amerongen, G.P., Duckers, H.J.
- ID
- ZDB-PUB-160130-7
- Date
- 2016
- Source
- Cardiovascular research 110(1): 129-39 (Journal)
- Registered Authors
- Bos, Frank
- Keywords
- Endothelial function, Intraplaque haemorrhage, THSD1, Vulnerable plaque
- MeSH Terms
-
- Animals
- Apolipoproteins E/deficiency
- Apolipoproteins E/metabolism
- Atherosclerosis/metabolism*
- Carotid Artery Diseases/metabolism
- Endothelial Cells/metabolism*
- Female
- Humans
- Male
- Mice, Inbred C57BL
- Microvessels/metabolism*
- Neovascularization, Pathologic/metabolism*
- Phosphatidylinositol 3-Kinases/metabolism
- Plaque, Atherosclerotic/pathology
- Thrombospondin 1/metabolism
- Thrombospondins/metabolism*
- PubMed
- 26822228 Full text @ Cardiovasc. Res.
Citation
Haasdijk, R.A., den Dekker, W.K., Cheng, C., Tempel, D., Szulcek, R., Bos, F.L., Hermkens, D.M., Chrifi, I., Brandt, M.M., van Dijk, C., Xu, Y.J., van de Kamp, E.H., Blonden, L.A., van Bezu, J., Sluimer, J.C., Biessen, E.A., van Nieuw Amerongen, G.P., Duckers, H.J. (2016) THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice. Cardiovascular research. 110(1):129-39.
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 vascularisation 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping