Abstract
Mutations in matrix Gla protein (MGP) have been correlated with vascular calcification. In the mouse model, MGP null vascular disease presents as calcifying cartilaginous lesions and mineral deposition along elastin lamellae (elastocalcinosis). Here we examined the mechanisms underlying both of these manifestations. Genetic ablation of enzyme transglutaminase 2 (TG2) in Mgp(-/-) mice dramatically reduced the size of cartilaginous lesions in the aortic media, attenuated calcium accrual more than 2-fold, and doubled longevity as compared with control Mgp(-/-) animals. Nonetheless, the Mgp(-/-);Tgm2(-/-) mice still died prematurely as compared with wild-type and retained the elastocalcinosis phenotype. This pathology in Mgp(-/-) animals was developmentally preceded by extensive fragmentation of elastic lamellae and associated with elevated serine elastase activity in aortic tissue and vascular smooth muscle cells. Systematic gene expression analysis followed by an immunoprecipitation study identified adipsin as the major elastase that is induced in the Mgp(-/-) vascular smooth muscle even in the TG2 null background. These results reveal a central role for TG2 in chondrogenic transformation of vascular smooth muscle and implicate adipsin in elastin fragmentation and ensuing elastocalcinosis. The importance of elastin calcification in MGP null vascular disease is highlighted by significant residual vascular calcification and mortality in Mgp(-/-);Tgm2(-/-) mice with reduced cartilaginous lesions. Our studies identify two potential therapeutic targets in vascular calcification associated with MGP dysfunction and emphasize the need for a comprehensive approach to this multifaceted disorder.
Highlights
matrix Gla protein (MGP) inhibits tissue calcification, but underlying mechanisms are understudied
The present study provides evidence for two mechanisms of arterial calcification in MGP null vascular disease
TG2independent elastocalcinosis is preceded by elastin fragmentation and associates with induction of the serine elastase adipsin
Summary
Results: In MGP null mice, TG2 ablation prevents calcifying cartilaginous vascular lesions but does not affect elastocalcinosis and elastin fragmentation associated with increased elastase adipsin. The Mgp؊/؊;Tgm2؊/؊ mice still died prematurely as compared with wild-type and retained the elastocalcinosis phenotype This pathology in Mgp؊/؊ animals was developmentally preceded by extensive fragmentation of elastic lamellae and associated with elevated serine elastase activity in aortic tissue and vascular smooth muscle cells. Restoring circulating levels of MGP in MgpϪ/Ϫ mice does not rescue the vascular phenotype, but re-establishment of MGP expression in VSMCs does prevent both cartilaginous lesions and calcium accrual [8], identifying VSMC-derived MGP as a potent local inhibitor of matrix mineralization and chondrogenic dedifferentiation of VSMCs in the arterial wall context. These data demonstrate that both chondrogenic transformation and elastin fragmentation contribute significantly to MGP null vascular disease and suggest that MGP has an unanticipated regulatory function during arterial development, controlling the expression of adipsin and stabilizing the structure of the vascular elastic lamellae
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