Angiotensin II promotes thoracic aortic dissections and ruptures in Col3a1 haploinsufficient mice.

Abstract

Vascular Ehlers-Danlos syndrome is a dramatic inherited disease caused by mutations of type III collagen (COL3A1) gene, associated with early-onset occurrence of arterial ruptures. Col3a1(+/-) heterozygous mice, the only vascular Ehlers-Danlos syndrome model available to date, have no spontaneous early vascular phenotype. Our objective was to determine the susceptibility of Col3a1(+/-) mice to develop arterial ruptures under high blood pressure (BP) conditions induced by a 4-week infusion of angiotensin II (AngII). AngII (1 μg/kg per minute) significantly and comparably increased systolic BP in Col3a1(+/-) and Col3a1(+/+) mice but led to a higher premature mortality rate in Col3a1(+/-) mice compared with Col3a1(+/+) mice (73% versus 36%; P=0.03), particularly during the first-week infusion (55% versus 0%). Echocardiography and histological analysis evidenced that early deaths were caused by thoracic aortic ruptures preceded by dissections and associated with low aortic collagen fibrils content. Remarkably, lowering the dose of AngII (0.5 μg/kg per minute) rescued the first-week premature deaths of Col3a1(+/-) mice while decreasing the rises in systolic BP (P=0.05 compared with the high-dose AngII), resulting in similar mortality rates in both groups of mice at the end of the 4-week period (30% versus 50% in Col3a1(+/-) and Col3a1(+/+) mice; P=0.30). Finally, norepinephrine infusion (3.9 μg/kg per minute) did not induced significant mortality in both groups, whereas it significantly increased systolic BP, comparably with the high and with the low dose of AngII in Col3a1(+/-) mice (P=0.53 and P=1.00, respectively). Our findings demonstrated the extreme sensitivity of Col3a1 insufficient mice to prematurely develop thoracic aortic ruptures in response to AngII and its associated high levels in BP.

• Authors: Julie Faugeroux, Hany Nematalla, Weiwei Li, Marc Clement, Estelle Robidel, Michael Frank, Emmanuel Curis, Hafid Ait-Oufella, Giuseppina Caligiuri, Antonino Nicoletti, Albert Hagege, Emmanuel Messas, Patrick Bruneval, Xavier Jeunemaitre, Sonia Bergaya
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 62 Issue 1 Pg. 203-8 (Jul 2013) ISSN: 1524-4563 [Electronic] United States
• PMID: 23630948 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL3A1 protein, human
• Collagen Type III
• Angiotensin II
• DNA

Topics

• Aortic Dissection (etiology, genetics, metabolism)
• Aneurysm, Ruptured
• Angiotensin II (administration & dosage, toxicity)
• Animals
• Aorta, Thoracic (drug effects, metabolism, pathology)
• Aortic Rupture (etiology, genetics, metabolism)
• Collagen Type III (blood, deficiency, genetics)
• DNA (genetics)
• DNA Mutational Analysis
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ehlers-Danlos Syndrome (complications, genetics, metabolism)
• Haploinsufficiency
• Infusions, Intravenous
• Mice
• Mutation