Thrombospondin-4 mediates cardiovascular remodelling in angiotensin II-induced hypertension

Cardiovasc Pathol. Jul-Aug 2018;35:12-19. doi: 10.1016/j.carpath.2018.03.003. Epub 2018 Apr 7.

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.

Keywords: aortic dissection; heart hypertrophy; perivascular fibrosis; thrombospondin 4.

MeSH terms

  • Aneurysm, Dissecting / chemically induced
  • Aneurysm, Dissecting / genetics
  • Aneurysm, Dissecting / metabolism*
  • Aneurysm, Dissecting / pathology
  • Angiotensin II*
  • Animals
  • Aorta / metabolism
  • Aorta / ultrastructure
  • Aortic Aneurysm / chemically induced
  • Aortic Aneurysm / genetics
  • Aortic Aneurysm / metabolism*
  • Aortic Aneurysm / pathology
  • Cardiomegaly / chemically induced
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Dilatation, Pathologic
  • Disease Models, Animal
  • Fibrillar Collagens / metabolism
  • Fibrillar Collagens / ultrastructure
  • Fibrosis
  • Hypertension / chemically induced
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Hypertension / pathology
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocardium / ultrastructure
  • Thrombospondins / deficiency
  • Thrombospondins / genetics
  • Thrombospondins / metabolism*
  • Vascular Remodeling*
  • Ventricular Remodeling*

Substances

  • Fibrillar Collagens
  • Thrombospondins
  • thrombospondin 4
  • Angiotensin II