cholecalciferol and Aortic-Aneurysm--Abdominal

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.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Apolipoproteins E; Blood Pressure; Caloric Restriction; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Humans; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Up-Regulation; Vitamin D Deficiency

Abdominal aortic aneurysms (AAAs) have traditionally been attributed to atherosclerosis, although there is increasing epidemiological, biochemical and genetic evidence that aneurysmal arterial disease is different from occlusive atherosclerosis. One of the most consistent biochemical findings in the aneurysmal aorta is a significant reduction in elastin protein; the cause, for this remains unclear. There is in vitro evidence that vitamin D3 (1,25 dihydrocholecalciferol) inhibits the production of elastin by smooth muscle cells. On the basis of this observation and the possibility that some subjects may be exposed to excess vitamin D3, the hypothesis that vitamin D3 may be a previously unrecognized aetiological factor in the pathogenesis of AAA is developed.

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Cholecalciferol; Elastin; Humans; Infant; Infant, Newborn; Models, Cardiovascular