Smooth Muscle Cells Give Rise to Osteochondrogenic Precursors and Chondrocytes in Calcifying Arteries

Abstract

Abstract-Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. To develop appropriate prevention and/or therapeutic strategies for vascular calcification, it is important to understand the origins of the cells that participate in this process. In this report, we used the SM22-Cre recombinase and Rosa26-LacZ alleles to genetically trace cells derived from smooth muscle. We found that smooth muscle cells (SMCs) gave rise to osteochondrogenic precursor-and chondrocyte-like cells in calcified blood vessels of matrix Gla protein deficient (MGP Ϫ/Ϫ ) mice. This lineage reprogramming of SMCs occurred before calcium deposition and was associated with an early onset of Runx2/Cbfa1 expression and the downregulation of myocardin and Msx2. There was no change in the constitutive expression of Sox9 or bone morphogenetic protein 2. Osterix, Wnt3a, and Wnt7a mRNAs were not detected in either calcified MGP Ϫ/Ϫ or noncalcified wild-type (MGP ϩ/ϩ ) vessels. Finally, mechanistic studies in vitro suggest that Erk signaling might be required for SMC transdifferentiation under calcifying conditions. These results provide strong support for the hypothesis that adult SMCs can transdifferentiate and that SMC transdifferentiation is an important process driving vascular calcification and the appearance of skeletal elements in calcified vascular lesions.

Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

“…15,24,31,32 Through a genetic fate mapping strategy, these cells were identified as transdifferentiated SMCs on their way to an osteoblastic fate prior to matrix calcification. 33 Deletion of Runx2 in vascular SMCs, therefore, prohibits osteoblastic differentiation and AMC, 22 consistent with the current findings of osteoblastic differentiation in LDLr À/À mice.…”

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

“…Jag1 +/− and Jag2 +/− mice were obtained from the Jackson Laboratory. Genotypes were confirmed by PCR (32)(33)(34), and experiments were performed with generations F4-F6. Littermates were used as wild-type controls.…”

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

“…However, it appears that the hallmarks of calcification induced by GlaMGP deficiency are not the same as in the warfarin-induced pathology. Genetic ablation of MGP leads to VC that is associated with chondrogenic transformation of the smooth muscle (16) and is mediated by activated BMP signaling (13,14,17). In contrast, warfarin-induced calcification of elastic lamellae in vivo does not involve ectopic chondrogenesis, and ex vivo studies indicate that it may not hinge on BMP activation (11).…”

“…Given the importance of activated ␤-catenin signaling in this type of calcification, we evaluated the bioflavonoid quercetin, capable of inhibiting this pathway (19 -21), as an attenuator of osteoblast-like transformation and mineralization in VSMCs. In addition, we examined whether ␤-catenin activation and quercetin effect depend on changes in GlaMGP levels and assessed potential interactions of the ␤-catenin pathway with BMP, Notch, and PKA pathways, which have previously been implicated in phosphate-induced calcification of VSMCs in vitro (16,22,23) and are known to interact with ␤-catenin signaling in diverse biological systems (24 -27).…”