The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens

Abstract

Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, vascular calcification has now emerged as a highly regulated form of biomineralization organized by collagenous and elastin extracellular matrices. During skeletal bone formation, paracrine epithelial-mesenchymal and endothelial-mesenchymal interactions control osteochondrocytic differentiation of multipotent mesenchymal progenitor cells. These paracrine osteogenic signals, mediated by potent morphogens of the BMP and Wnt superfamilies, are also active in the programming of arterial osteoprogenitor cells during vascular and valve calcification. Inflammatory cytokines, reactive oxygen species and oxylipids – increased in the clinical settings of atherosclerosis, diabetes, and uremia that promote arteriosclerotic calcification – elicit the ectopic vascular activation of osteogenic morphogens. Specific extracellular and intracellular inhibitors of BMP-Wnt signaling have been identified as contributing to the regulation of osteogenic mineralization during development and disease. These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis.

In Situ Vascular Tissue Remodeling Using Biodegradable Tubular Scaffolds With Incorporated Growth Factors and Chemoattractant Molecules

“…Other data indicate that the occurrence of ectopic medial calcifications is associated with adventitious cells [17]. Vessel and valve endothelial cells serve as a cellular barrier between the blood and the main tissue components, but participate in the endothelial-mesenchymal transition, playing a key role in tissue fibrosis and calcification [18]. In vitro and ex vivo studies have established the involvement of inflammation in the calcification of both valves and vessels [19,20].…”

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

“…PKA, BMP, ERK, and Notch pathways and inflammatory cytokine signaling have been linked to VC induced by elevated phosphate or by diabetic milieu (22,36,39,40), whereas ␤-catenin activity is critical in warfarin-induced VSMC mineralization (18) and has been implicated in both diabetic calcification (41) and calcification of the heart valves (42). Based on the perceived mechanistic similarity between pathological and physiological calcification, C/EBP, JNK, and pRb pathways associated with osteogenesis (43-45) may also contribute to vascular mineralization.…”

Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

“…It has been demonstrated in animal models that VC may be induced by stimulating various genes, including bone morphogenetic protein (BMP)2, BMP4 (2,3), runt-related transcription factor (RUNX)2 and alkaline phosphatase (ALP) (4). Previous studies have revealed that BMP2 and BMP4, members of the transforming growth factor-b cytokine superfamily, participate in vascular calcification (5). Vascular endothelial and smooth muscle are key sources of BMPs, which when detected in calcified blood vessels may be associated with enhanced vascular calcification (6).…”