Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome.

Abstract

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an 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 vascular Ehlers-Danlos syndrome.

• Authors: Anne Legrand, Charline Guery, Julie Faugeroux, Erika Fontaine, Carole Beugnon, Amélie Gianfermi, Irmine Loisel-Ferreira, Marie-Christine Verpont, Salma Adham, Tristan Mirault, Juliette Hadchouel, Xavier Jeunemaitre
• Journal: PLoS genetics (PLoS Genet) Vol. 18 Issue 3 Pg. e1010059 (03 2022) ISSN: 1553-7404 [Electronic] United States
• PMID: 35245290 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type III

Topics

• Animals
• Aortic Rupture (genetics, prevention & control)
• Arteries
• Collagen Type III (genetics)
• Disease Models, Animal
• Ehlers-Danlos Syndrome (drug therapy, genetics)
• Humans
• Male
• Mice