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Vascular calcification is dependent on plasma levels of pyrophosphate.

Lomashvili KA, Narisawa S, Millán JL, O'Neill WC - Kidney Int. (2014)

Bottom Line: However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels.Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification.Histology revealed medial calcification with no signs of rejection.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels. This was tested in an animal model in which aortas were transplanted between normal mice and Enpp1(-/-) mice lacking ectonucleotide pyrophosphatase phosphodiesterase, the enzyme that synthesizes extracellular pyrophosphate. Enpp1(-/-) mice had very low plasma pyrophosphate and developed aortic calcification by 2 months that was greatly accelerated with a high-phosphate diet. Aortas of Enpp1(-/-) mice showed no further calcification after transplantation into wild-type mice fed a high-phosphate diet. Aorta allografts of wild-type mice calcified in Enpp1(-/-) mice but less so than the adjacent recipient Enpp1(-/-) aorta. Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification. Histology revealed medial calcification with no signs of rejection. Thus, normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification, and systemic Enpp1 deficiency is sufficient to produce vascular calcification despite normal vascular extracellular pyrophosphate production. This establishes an important role for circulating extracellular pyrophosphate in preventing vascular calcification.

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Histology of aortic allografts. Left-hand column: normal mouse aorta. Right-hand column: wild-type allograft in wild-type mouse 5 months after transplantation. Top row: hematoxylin and eosin stain. Middle row: elastin stain. Bottom row: trichrome stain.
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Figure 4: Histology of aortic allografts. Left-hand column: normal mouse aorta. Right-hand column: wild-type allograft in wild-type mouse 5 months after transplantation. Top row: hematoxylin and eosin stain. Middle row: elastin stain. Bottom row: trichrome stain.

Mentions: To determine the extent to which this difference in plasma ePPi influenced vascular calcification, calcification was examined in aortas transplanted between Enpp1−/− and wild-type mice. Aortas were transplanted orthotopically from 2 month-old mice into the infra-renal portion of the abdominal aorta of littermates, after which the mice were fed a 1.5% phosphorus diet for another 2 months. Operative mortality was as follows: WT allografts into WT, 2 out of 10; Enpp1−/− allografts into WT, 0 out of 8; Enpp1−/− allografts into Enpp1−/−, 3 out of 15; WT allografts into Enpp1−/−, 1 out of 8. In total, WT recipients had an 11% mortality while Enpp1−/− recipients had a 17% mortality, due entirely to graft thrombosis. There was no delayed mortality. The mice were otherwise healthy and transplantation did not affect aortic structure (Fig. 4). Specifically, there was no intimal thickening, cellular infiltration, or fibrosis suggestive of rejection. Alizarin red stains of representative aortic allografts and recipient aortas 2 months after transplantation are shown in Figure 5 while quantitative data are provided in Figure 6A. There was no calcification of wild-type allografts placed into wild-type recipients, indicating that transplantation alone does not induce calcification. Wild-type allografts had a significantly greater calcium content when placed into Enpp1−/− recipients than into wild-type recipients (49.3 ± 15.0 nmol/mg vs. 14.4 ± 3.1 nmol/mg; p=0.039) but the content was far lower than in the adjacent recipient Enpp1−/− aorta or in Enpp1−/− allografts placed in Enpp1−/− mice. Enpp1−/− allografts transplanted into WT mice showed a small amount of calcification but this did not differ from that present in Enpp1−/− aortas at 2 months of age, the time of harvest for transplantation (32.7 ± 7.2 nmol/mg vs. 28.9 ± 9.0 nmol/mg). Thus there was no increase after transplantation. There was extensive calcification of Enpp1−/− allografts in Enpp1−/− mice that did not differ from the recipient aortas, indicating that transplantation did not suppress calcification. As shown in Figures 6B and 6C, the histologic pattern of calcification was identical in Enpp1 allografts and recipient aortas. Thus, transplantation per se did not affect calcification.


Vascular calcification is dependent on plasma levels of pyrophosphate.

Lomashvili KA, Narisawa S, Millán JL, O'Neill WC - Kidney Int. (2014)

Histology of aortic allografts. Left-hand column: normal mouse aorta. Right-hand column: wild-type allograft in wild-type mouse 5 months after transplantation. Top row: hematoxylin and eosin stain. Middle row: elastin stain. Bottom row: trichrome stain.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4308968&req=5

Figure 4: Histology of aortic allografts. Left-hand column: normal mouse aorta. Right-hand column: wild-type allograft in wild-type mouse 5 months after transplantation. Top row: hematoxylin and eosin stain. Middle row: elastin stain. Bottom row: trichrome stain.
Mentions: To determine the extent to which this difference in plasma ePPi influenced vascular calcification, calcification was examined in aortas transplanted between Enpp1−/− and wild-type mice. Aortas were transplanted orthotopically from 2 month-old mice into the infra-renal portion of the abdominal aorta of littermates, after which the mice were fed a 1.5% phosphorus diet for another 2 months. Operative mortality was as follows: WT allografts into WT, 2 out of 10; Enpp1−/− allografts into WT, 0 out of 8; Enpp1−/− allografts into Enpp1−/−, 3 out of 15; WT allografts into Enpp1−/−, 1 out of 8. In total, WT recipients had an 11% mortality while Enpp1−/− recipients had a 17% mortality, due entirely to graft thrombosis. There was no delayed mortality. The mice were otherwise healthy and transplantation did not affect aortic structure (Fig. 4). Specifically, there was no intimal thickening, cellular infiltration, or fibrosis suggestive of rejection. Alizarin red stains of representative aortic allografts and recipient aortas 2 months after transplantation are shown in Figure 5 while quantitative data are provided in Figure 6A. There was no calcification of wild-type allografts placed into wild-type recipients, indicating that transplantation alone does not induce calcification. Wild-type allografts had a significantly greater calcium content when placed into Enpp1−/− recipients than into wild-type recipients (49.3 ± 15.0 nmol/mg vs. 14.4 ± 3.1 nmol/mg; p=0.039) but the content was far lower than in the adjacent recipient Enpp1−/− aorta or in Enpp1−/− allografts placed in Enpp1−/− mice. Enpp1−/− allografts transplanted into WT mice showed a small amount of calcification but this did not differ from that present in Enpp1−/− aortas at 2 months of age, the time of harvest for transplantation (32.7 ± 7.2 nmol/mg vs. 28.9 ± 9.0 nmol/mg). Thus there was no increase after transplantation. There was extensive calcification of Enpp1−/− allografts in Enpp1−/− mice that did not differ from the recipient aortas, indicating that transplantation did not suppress calcification. As shown in Figures 6B and 6C, the histologic pattern of calcification was identical in Enpp1 allografts and recipient aortas. Thus, transplantation per se did not affect calcification.

Bottom Line: However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels.Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification.Histology revealed medial calcification with no signs of rejection.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels. This was tested in an animal model in which aortas were transplanted between normal mice and Enpp1(-/-) mice lacking ectonucleotide pyrophosphatase phosphodiesterase, the enzyme that synthesizes extracellular pyrophosphate. Enpp1(-/-) mice had very low plasma pyrophosphate and developed aortic calcification by 2 months that was greatly accelerated with a high-phosphate diet. Aortas of Enpp1(-/-) mice showed no further calcification after transplantation into wild-type mice fed a high-phosphate diet. Aorta allografts of wild-type mice calcified in Enpp1(-/-) mice but less so than the adjacent recipient Enpp1(-/-) aorta. Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification. Histology revealed medial calcification with no signs of rejection. Thus, normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification, and systemic Enpp1 deficiency is sufficient to produce vascular calcification despite normal vascular extracellular pyrophosphate production. This establishes an important role for circulating extracellular pyrophosphate in preventing vascular calcification.

Show MeSH
Related in: MedlinePlus