Long-term effects of losartan on structure and function of the thoracic aorta in a mouse model of Marfan syndrome

Background and purpose:

During development of thoracic aortic aneurysms in a mouse model of Marfan syndrome, upregulation of matrix metalloproteinase (MMP)-2 and -9 was accompanied by compromised aortic constriction and endothelium-dependent relaxation. Losartan has been proposed for the prevention of thoracic aortic aneurysm. We hypothesized that losartan would suppress MMP-2/-9 activation and improve aortic vasomotor function in this model.

Experimental approach:

A well-characterized mouse model of Marfan syndrome (Fbn1^C1039G/+) was used. Starting at 6 weeks old, Marfan mice were untreated or given losartan (0.6 g·L⁻¹ in drinking water, n= 30). The littermate Fbn1^+/+ mice served as control. Thoracic aortas were studied at 3, 6 and 9 months by histology and by contractility assays in isolated segments in vitro.

Key results:

Losartan improved elastic fibre organization and increased aortic breaking stress. Losartan reduced the activity and protein expression of MMP-2 and MMP-9 at all ages. Aortic constriction in response to membrane depolarization or phenylephrine was increased by losartan at 3 and 9 months by 100–200%. Active force of aortic smooth muscle was also increased at 6 and 9 months. Acetylcholine-induced endothelium-dependent relaxation was improved by 30% after 3 months of losartan treatment, but such improvement disappeared with longer duration of treatment, accompanied by reduced phosphorylation of endothelial nitric oxide (NO) synthase^Ser1177, Akt^Thr308 and Akt^Ser473, compared with the control.

Conclusions and implications:

Losartan improved the contractile function of aorta and reduced MMP activation. However, the endothelial NO pathway remained suppressed in the thoracic aorta during losartan treatment, which might limit its long-term benefits in Marfan syndrome.