Arterial Elastin Abundance, Rather Than Orthologue Origin, Modulates Medial Arterial Calcification in Matrix Gla Protein-Deficient Mice

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Abstract Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. While medial calcification and physiologic ‘hard’ tissue mineralization in the skeleton are both regulated by several common determinants, emerging data suggest that there might be fundamental differences in the mechanisms underlying these two processes. Objective We previously demonstrated that elastin haploinsufficiency delays medial calcification in MGP-deficient mice. Here, using mice in which a human ELN transgene rescues mouse elastin deficiency, we investigated whether the origin and abundance of arterial elastin differentially affect the initiation and progression of medial calcification. Approach and Results We pursued a transgenic approach to alter the arterial elastin scaffold in MGP-deficient mice. Our analyses of a humanized MGP-deficient model with 40% reduction of medial elastin content showed a complete absence of the early-stage vascular calcification. Additionally, we showed that mouse and human elastin orthologues affect vascular calcification in a comparable manner. Conclusion Arterial elastin abundance, rather than orthologue origin, modulates the initiation and progression of medial calcification in MGP-deficient mice. A further reduction in arterial elastin beyond that achieved by elastin haploinsufficiency profoundly delays mineral deposition and maturation, whereas restoration of elastin abundance through transgenic human ELN expression restores arterial calcification.

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