Reversibility of Calcitriol-Induced Medial Artery Calcification in Rats With Intact Renal Function

Abstract

VC is an important clinical entity; however, very little information is available on its resolution. Induction and regression of calcitriol-induced VC was studied in 47 rats. After calcitriol withdrawal, there was a relatively rapid regression of VC mediated by an active cellular process.Introduction: Vascular calcifications (VCs) represent an important risk factor for cardiovascular death. Although VCs are prevalent in relevant diseases (e.g., chronic kidney disease, osteoporosis, diabetes), the reversibility of extraskeletal calcifications is an unresolved issue. This study was conducted to investigate (1) the in vivo effect of calcitriol on VC and (2) whether calcitriol-induced VC would regress after suppression of calcitriol treatment. Materials and Methods:The calcifying effect of calcitriol was studied in four groups of rats (n ‫ס‬ 8) that received calcitriol (1 g/kg, IP) for 2, 4, 6, and 8 days. The reversibility of VC was studied in three additional groups (n ‫ס‬ 5) treated with 1 g/kg of calcitriol for 8 days that were subsequently killed 1, 2, and 9 weeks after the last calcitriol dose. Aortic VC was assessed by histology and by quantification of aortic calcium and phosphorus content. The aortic wall was studied by histology and immunohistochemistry. Statistical analysis was performed by ANOVA and t-tests. Results: Calcitriol administration resulted in a time-dependent induction of VC, with aortic calcium and phosphorus being significantly increased at 6 and 8 days. Treatment with calcitriol for 8 days resulted in massive medial calcification of the aorta with a 10-to 30-fold increase in the aortic Ca and P content. After suppressing calcitriol administration, a progressive decrease in von Kossa staining and aortic Ca (from 32.8 ± 2.5 to 9.3 ± 1.8 mg/g of tissue, p < 0.001) and P (from 11.9 ± 1.2 to 2.7 ± 1.8 mg/g of tissue, p ‫ס‬ 0.001) content was evidenced. Histology of the aortic wall showed monocytes adhered to the aortic endothelium and macrophages involved in the reabsorption of calcium deposits. Conclusions: Our results show that calcitriol treatment induces time-dependent VC. After calcitriol withdrawal, VC regress rapidly with aortic calcium and phosphorus decreasing by 75% in the course of 9 weeks. An active cellular process seems to be involved in regression of VC.

Calcium and vitamin D intakes may be positively associated with brain lesions in depressed and nondepressed elders

“…High intakes of calcium were found to be associated with coronary artery calcification in a small sample (n=39) of young adults with end-stage renal disease [15]. Administration to rats (n=47) of calcitriol, the hormonal form of vitamin D, was found to cause vascular calcification [16].…”

“…The importance of diet to brain lesions remains uncertain. In small studies high doses of calcium and vitamin D have been associated with vascular calcification [15,16]. High intakes of calcium were found to be associated with coronary artery calcification in a small sample (n=39) of young adults with end-stage renal disease [15].…”

Vitamin D Affects Survival Independently of Vascular Calcification in Chronic Kidney Disease

“…Furthermore, CKD progression exposes patients to a particular risk of developing both 25D and 1,25D deficiencies (17,18). In animal models, exogenous administration of supraphysiological doses of VDR activators has been associated with both the incidence and progression of vascular calcification (19,20), whereas the administration of VDR activators at more physiologic doses (i.e., just enough to correct secondary hyperparathyroidism) protect against aortic calcification (21). In a CKD setting, a recent study in adult hemodialysis patients described an association between 25D deficiency and arterial stiffness (13), whereas dialyzed children showed a bimodal association between 1,25D levels and vascular calcification and stiffness (22).…”

Effect of Crystallization Inhibitors on Vascular Calcifications Induced by Vitamin D A Pilot Study in Sprague-Dawley Rats

“…[7][8][9] A common characteristic of the proteins involved in calcification is calcium ion affinity, and there are 2 major groups of such proteins: phosphoproteins and carboxyproteins. Major phosphoproteins include osteopontin [10][11][12][13] and osteoprotegerin, [14][15][16] and a major carboxyprotein is matrix Gla protein [17][18][19] or bone-Gla-protein, also known as osteocalcin.…”