title: Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms.
abstract: Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout (Thbs4(-/-)) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4(-/-) mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4(-/-) mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4(-/-) mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4(-/-) mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.
authors.affiliation: Departments of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands;
authors.forename: Teresa
authors.initials: T
authors.lastname: Palao
authors.affiliation: Experimental Medical Science, Lund University, Lund, Sweden; and.
authors.forename: Catarina
authors.initials: C
authors.lastname: Rippe
authors.affiliation: Cell Biology and Histology, Core Facility Cellular Imaging, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: van Veen
authors.affiliation: Departments of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands;
authors.forename: Ed
authors.initials: E
authors.lastname: VanBavel
authors.affiliation: Experimental Medical Science, Lund University, Lund, Sweden; and.
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.affiliation: Departments of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands; n.t.bakker@amc.uva.nl.
authors.forename: Erik N T P
authors.initials: EN
authors.lastname: Bakker
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010641:Phenotype; D019699:Thrombospondins / Q000172:deficiency* / Q000235:genetics; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D019699:Thrombospondins; D014665:Vasodilator Agents; C101864:thrombospondin 4; D000804:Angiotensin II; D003094:Collagen
keywords: aneurysm; endothelial dysfunction; heart hypertrophy; hypertension; small arteries; thrombospondin-4