Regulation of In Vitro Vascular Calcification by BMP4, VEGF and Wnt3a

Abstract

Vascular calcification is a common clinical complication of cardiovascular disease, diabetes and end-stage renal failure, associated with significant morbidity and mortality. In this study we demonstrate that factors secreted by the hypertrophic chondrocytes induce matrix mineralization and osteoblastic transformation in cultured mouse vascular smooth muscle cells (VSMCs). In addition, these factors render VSMCs responsive to BMP4 and Wnt3a ligands. Neither BMP-4 nor Wnt3a could induce mineralization in short-term (up to 8 days) cultures of primary mouse VSMCs. However, both ligands act synergistically with the chondrocyte-conditioned medium causing a further increase in VSMC calcification. Finally, we show that commitment of VSMCs towards the BMP-regulated mineralization can be induced by the chondrocyte-secreted bone anabolic factor VEGF. In addition, expression profiling suggests a novel role in vascular calcification for the matrix proteins previously known to regulate bone formation and mineralization (including MMP3, fibulin, 11betahydroxysteroid dehydrogenase 1 and retinoic acid receptor responder 2). The results of this study may contribute to further understanding of the cellular mechanisms responsible for vascular calcification and provide important information for the treatment of this pathology.

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

“…Although the comprehensive study of cell signaling in warfarin-induced calcification of VSMCs presented here converged on the critical role of ␤-catenin pathway, it is noteworthy that activation of ␤-catenin per se is not sufficient to induce calcification in the absence of other stimuli (53). Further studies are needed to identify additional mechanism(s) acting in concert with ␤-catenin signaling to orchestrate osteogenic transformation and calcification in VSMCs.…”

RANKL Increases Vascular Smooth Muscle Cell Calcification Through a RANK-BMP4–Dependent Pathway

“…34 In addition, BMP4 has been involved in the osteogenic transition of VSMCs, leading to vascular calcification. 35 It has also been described that BMP4 increases in vitro VSMC calcification 36 and is upregulated in calcified atherosclerotic lesions. 13 Our results further show that parallel to a decrease in vascular calcification, inhibition of the alternative NF-B activation pathway also decreased BMP4.…”

Mechanistic Insights into Vascular Calcification in CKD

“…Indeed, VEGF-A promotes the BMP-induced mineralization of cultured VSMC. 90 VEGF-A and Ang could modulate calcification by affecting endothelia through binding to VEGFR1/2 or Tie-2, respectively, leading to changes in vasodilators or vasoconstrictors. Alternatively, there is evidence that VEGF and Ang receptors are expressed on VSMCs themselves 91,92 ; therefore, vascular growth factors may directly alter the biology of these cells (Figure 4).…”