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- Palao, Teresa, et al.
(författare)
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Thrombospondin-4 knockout in hypertension protects small artery endothelial function but induces aortic aneurysms.
- 2016
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Ingår i: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 310:11, s. 1486-1493
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Tidskriftsartikel (refereegranskat)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 (ER) stress response in the heart. In this study we explored the role of TSP-4 in hypertension. For this purpose, wild type (WT) and thrombospondin-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 WT 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.
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- Palao, Teresa, et al.
(författare)
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Thrombospondin-4 mediates cardiovascular remodelling in angiotensin II-induced hypertension
- 2018
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Ingår i: Cardiovascular Pathology. - : Elsevier BV. - 1054-8807. ; 35, s. 12-19
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Tidskriftsartikel (refereegranskat)abstract
- Thrombospondin 4 (TSP-4) expression is induced in the heart and vasculature under pathological conditions, including myocardial infarction, myocardial pressure overload, and hypertension. TSP-4 is linked to remodelling processes, where it may affect extracellular matrix protein organization. In previous work, we studied the role of TSP-4 in small arteries during hypertension using Ang II-treated Thrombospondin 4 knockout (Thbs4−/−) mice. We reported increased heart weight, as well as the occurrence of aortic aneurysms in the Ang II-treated Thbs4−/− animals. In the present study, we further characterized the hearts and aortas from these animals. Hypertrophy of cardiomyocytes, together with perivascular fibrosis and inflammation was observed in the Ang II-treated Thbs4−/− hearts. In the aortas, an increase in the aortic wall cross-sectional area (CSA) and wall thickness of the Ang II-treated Thbs4−/− mice was found. More detailed investigation of the Ang II-treated Thbs4−/− aortas also revealed the appearance of aortic dissections in the outer medial layer of the arteries, as well as pronounced inflammation. No differences were found in several other extracellular matrix-related parameters, such as number of elastin breaks or stress–strain relationships. However, at the ultrastructural level, collagen fibers showed alterations in diameter in the media and adventitia of the Ang II-treated Thbs4−/− mice, in the area prone to dissection. In conclusion, we identified TSP-4 as an important protein in the development of cardiac hypertrophy and aortic dissections in Ang II-induced hypertension.
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