Intimal macrophage infiltration and osteogenic differentiation of vascular smooth muscle cells (VSMC) contribute significantly to the pathogenesis of atherosclerosis. However, little is known about the crosstalk between these two major cell types in atherosclerotic lesions. In the past funding period, we have identified a definitive role of smooth muscle cell (SMC)-expressed osteogenic transcription factor Runx2 in regulating osteogenic differentiation of VSMC and vascular calcification in atherosclerosis. Moreover, we have identified a positive correlation between VSMC calcification and macrophage infiltration and formation of vascular osteoclasts (vOC) in atherosclerotic lesions. Although osteoclast-like cells were observed previously in atherosclerotic lesions, the mechanisms of formation and function of vOC in atherosclerosis is unknown. Our studies have identified an important new role of SMC-expressed Runx2-dependent expression of RANKL, the key regulator for osteoclastogenesis, in promoting macrophage infiltration and vOC formation. The known function of osteoclasts is to resorb bone mineral. The observation of osteoclastic proteases around the calcified atherosclerotic lesions suggests that vOC may function to resorb vascular calcification. Paradoxically, the anti-resorption bisphosphonate drugs have been shown to inhibit vascular calcification. The opposite effects of anti-resorbing drugs on the skeletal and vascular systems suggest different intrinsic signals and tissue-specific microenvironments that differentially govern the mineralization in bone and in the vasculature. Our finding of an intrinsi coupling between vOC and calcification supports a novel paradigm that vOC promotes vascular calcification. Preliminary studies demonstrated that osteoclasts promoted migration and osteogenic differentiation of progenitor cells, supporting a pro-osteogenic function of osteoclasts. Therefore, we hypothesize that vascular osteoclasts induce recruitment and calcification of osteogenic progenitor cells that promote vascular calcification in atherosclerosis Two Aims are proposed.
Aim 1 is to determine the function of vascular osteoclasts in regulating vascular calcification in vivo.
Aim 2 is to elucidate the mechanisms of vascular osteoclasts in regulating vascular calcification. Our published results and preliminary data strongly support the role of vOC in regulating vascular calcification in atherosclerosis. With a multidisciplinary team with established expertise in vascular, osteoclast and stem cell biology, new animal models, cutting-edge technologies and innovative approaches, the proposal will determine for the first time the function of vOC in regulating pathogenesis of vascular calcification in atherosclerosis, and elucidate the paradigm-shifting mechanisms. The novel insights gained in these studies may not only improve our understanding of basic mechanisms of vascular calcification, but also provide guidance for developing novel anti-coupling drugs to prevent and treat vascular calcification in atherosclerosis.

Public Health Relevance

Our published studies have supported an essential role of SMC-expressed Runx2 in regulating VSMC calcification and the formation of vascular osteoclasts (vOC), and further elucidated Runx2-regulated RANKL in VSMC as the key regulator for macrophage infiltration and vOC formation in atherosclerosis. These studies and our newly generated unique mouse models have laid a solid foundation for us to determine the function of vOC in regulating vascular calcification in vivo, and elucidate vOC-regulated calcification of osteogenic progenitors as emerging novel mechanisms of atherosclerotic calcification. The novel insights gained in these studies may not only improve our understanding of basic mechanisms of vascular calcification, but also provide guidance to the use of anti-coupling drugs to prevent and treat vascular calcification in atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL092215-06A1
Application #
8983268
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2009-04-01
Project End
2019-04-30
Budget Start
2015-06-24
Budget End
2016-04-30
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Su, Hairui; Sun, Chiao-Wang; Liu, Szu-Mam et al. (2018) Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1. Blood Adv 2:2829-2836
Yang, Youfeng; Sun, Yong; Chen, Jianye et al. (2018) AKT-independent activation of p38 MAP kinase promotes vascular calcification. Redox Biol 16:97-103
Sun, Yong; Byon, Chang Hyun; Yang, Youfeng et al. (2017) Dietary potassium regulates vascular calcification and arterial stiffness. JCI Insight 2:
Byon, Chang Hyun; Heath, Jack M; Chen, Yabing (2016) Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol 9:244-253
Tran, Ngoc-Tung; Su, Hairui; Khodadadi-Jamayran, Alireza et al. (2016) The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Rep 17:887-900
Ma, Liping; Ambalavanan, Namasivayam; Liu, Hui et al. (2016) TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling. Front Biosci (Landmark Ed) 21:397-409
Byon, Chang Hyun; Chen, Yabing (2015) Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep 13:206-15
Deng, Liang; Huang, Lu; Sun, Yong et al. (2015) Inhibition of FOXO1/3 promotes vascular calcification. Arterioscler Thromb Vasc Biol 35:175-83
Heath, Jack M; Sun, Yong; Yuan, Kaiyu et al. (2014) Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res 114:1094-102
Sun, Yong; Byon, Chang Hyun; Yuan, Kaiyu et al. (2012) Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 111:543-52

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