Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model.

Abstract

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

• Authors: Vianne Nsengiyumva, Smriti M Krishna, Corey S Moran, Joseph V Moxon, Susan K Morton, Michael W Clarke, Sai-Wang Seto, Jonathan Golledge
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 134 Issue 18 Pg. 2521-2534 (09 30 2020) ISSN: 1470-8736 [Electronic] England
• PMID: 32936248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Author(s).

Chemical References

• Adaptor Proteins, Signal Transducing
• Apolipoproteins E
• Sost protein, mouse
• Angiotensin II
• Cholecalciferol

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Angiotensin II
• Animals
• Aorta, Abdominal (drug effects, metabolism, pathology, physiopathology)
• Aortic Aneurysm, Abdominal (drug therapy, etiology, physiopathology)
• Aortic Rupture (drug therapy, etiology, physiopathology)
• Apolipoproteins E (deficiency)
• Blood Pressure (drug effects)
• Caloric Restriction
• Cholecalciferol (pharmacology, therapeutic use)
• Dietary Supplements
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation (drug effects)
• Humans
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Up-Regulation (drug effects)
• Vitamin D Deficiency (complications, physiopathology)