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Am J Physiol Heart Circ Physiol. 2016 Jun 1;310(11):H1486-93. doi: 10.1152/ajpheart.00046.2016. Epub 2016 Mar 11.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms.

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Departments of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands;
Experimental Medical Science, Lund University, Lund, Sweden; and.
Cell Biology and Histology, Core Facility Cellular Imaging, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
Departments of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands;


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.


aneurysm; endothelial dysfunction; heart hypertrophy; hypertension; small arteries; thrombospondin-4

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