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Mechanical strain-induced human vascular matrix synthesis: The role of angiotensin II

Cardiovascular Research Institute University of Leicester Leicester, UK, as90{at}le.ac.uk

Hash Patel

Cardiovascular Research Institute University of Leicester Leicester, UK

Abigail L Knight

Cardiovascular Research Institute University of Leicester Leicester, UK

Bryan Williams

Cardiovascular Research Institute University of Leicester Leicester, UK

Introduction: Reduced vascular compliance in patients with hypertension results from an increase in extra-cellular matrix (ECM) protein deposition in blood vessels. At least two key factors, namely mechanical strain and neurohumoral mediators, for example Angiotensin II (Ang II), promote fibrogenesis within vessel walls; however potential interactions between these have not been clearly defined. This work examined the direct effect of mechanical strain on matrix mRNA expression and protein synthesis by human vascular smooth muscle (VSM) cells and identified the importance of renin-angiotensin system (RAS) activation in stretch-induced matrix production.

Methods: Human VSM cells were exposed either to a cyclical mechanical strain regimen or to Ang II in the presence or absence of the Ang II receptor (AT₁ R) antagonist losartan or its more potent metabolite EXP3174. Analysis of matrix mRNA expression (Northerns) and protein synthesis (ELISA) and cellular AT₁-receptor protein expression (Westerns) were determined.

Results: Ang II increased both collagen 1 (92%, SEM +/-20%) mRNA expression and fibronectin (21% +/- 6%) protein synthesis in static VSM cells compared with unstimulated controls.The effect of Ang II was attenuated by antagonism of the AT ₁-receptor (AT₁ R). Similarly, mechanical strain induced an increase in both collagen 1 (102% +/- 30%) mRNA expression and fibronectin (50% +/-21%) protein synthesis. Surprisingly, in the absence of exogenous Ang II, AT₁-receptor blockade attenuated this stretch-induced increase in matrix synthesis. Mechanical strain also induced an increase in total cellular AT₁-receptor protein (30.7% +/- 3.5%) compared with static cells.

Conclusion: Both mechanical strain and Ang II increased matrix gene expression and protein synthesis by human VSM cells. The effect of strain was attenuated by AT ₁-receptor antagonism. Our results further suggest that mechanical strain may sensitise human VSM cells to the fibrogenic actions of Ang II, perhaps via upregulation of the AT₁-receptor.

Key Words: angiotensin II • mechanical strain • vascular smooth muscle cells • angiotensin receptors • vascular matrix

Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 1, 32-35 (2000)
DOI: 10.3317/jraas.2000.007


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