title: THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Remco A
authors.initials: RA
authors.lastname: Haasdijk
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Wijnand K
authors.initials: WK
authors.lastname: Den Dekker
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Regenerative Vascular Medicine Laboratory, Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3584 CX Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Szulcek
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Bos
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Hermkens
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Regenerative Vascular Medicine Laboratory, Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3584 CX Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Chrifi
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Regenerative Vascular Medicine Laboratory, Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3584 CX Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Maarten M
authors.initials: MM
authors.lastname: Brandt
authors.affiliation: Regenerative Vascular Medicine Laboratory, Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3584 CX Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Van Dijk
authors.affiliation: Regenerative Vascular Medicine Laboratory, Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3584 CX Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Yan Juan
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Esther H M
authors.initials: EH
authors.lastname: Van De Kamp
authors.affiliation: Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Lau A J
authors.initials: LA
authors.lastname: Blonden
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bezu
authors.affiliation: Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.affiliation: Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Geerten P
authors.initials: GP
authors.lastname: Van Nieuw Amerongen
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands h.j.duckers@umcutrecht.nl.
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism; D019699:Thrombospondins / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; C511241:THSD1 protein, human; D019700:Thrombospondin 1; D019699:Thrombospondins; C511242:Tmtsp protein, mouse; D019869:Phosphatidylinositol 3-Kinases
keywords: Endothelial function; Intraplaque haemorrhage; THSD1; Vulnerable plaque