دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice.
المؤلفون: Haasdijk RA; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands., Den Dekker WK; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands., Cheng C; 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., Tempel D; Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands., Szulcek R; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands., Bos FL; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Hubrecht Institute, Utrecht, The Netherlands., Hermkens DM; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Hubrecht Institute, Utrecht, The Netherlands., Chrifi I; 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., Brandt MM; 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., Van Dijk C; 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., Xu YJ; 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., Van De Kamp EH; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands., Blonden LA; Department of Cardiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands., Van Bezu J; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands., Sluimer JC; Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands., Biessen EA; Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands., Van Nieuw Amerongen GP; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, The Netherlands., Duckers HJ; Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands h.j.duckers@umcutrecht.nl.
المصدر: Cardiovascular research [Cardiovasc Res] 2016 May 01; Vol. 110 (1), pp. 129-39. Date of Electronic Publication: 2016 Jan 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : Oxford : Oxford Journals
Original Publication: London, British Medical Assn.
مواضيع طبية MeSH: Atherosclerosis/*metabolism , Endothelial Cells/*metabolism , Microvessels/*metabolism , Neovascularization, Pathologic/*metabolism , Thrombospondins/*metabolism, 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
مستخلص: 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.)
فهرسة مساهمة: Keywords: Endothelial function; Intraplaque haemorrhage; THSD1; Vulnerable plaque
المشرفين على المادة: 0 (Apolipoproteins E)
0 (THSD1 protein, human)
0 (Thrombospondin 1)
0 (Thrombospondins)
0 (Tmtsp protein, mouse)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
تواريخ الأحداث: Date Created: 20160130 Date Completed: 20161230 Latest Revision: 20220311
رمز التحديث: 20231215
DOI: 10.1093/cvr/cvw015
PMID: 26822228
قاعدة البيانات: MEDLINE
الوصف
تدمد:1755-3245
DOI:10.1093/cvr/cvw015