Abstract

We created a knock-in Col3a1+/G182R mouse model with spontaneous mortality caused by thoracic aortic rupture that recapitulates a rare vascular genetic disease of type III collagen, the vascular Ehlers-Danlos syndrome (vEDS). Investigation of this model showed lower survival rate in males caused by aortic rupture, thin non-inflammatory arteries and altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vEDS.