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Molecular regulation of vascular calcification in atherosclerosis

动脉粥样硬化血管钙化的分子调控

基本信息

批准号：
9264578
负责人：
Yabing Chen
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264578
关键词：
Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Blood Vessels Calcified Cells Coupling Data Exhibits Foundations Funding Genetic High Fat Diet Impairment Infiltration Minerals Modeling Molecular Mus Muscle Cells Mutant Strains Mice Mutation Osteoclasts Osteogenesis Pathogenesis Peptide Hydrolases Pharmaceutical Preparations Publishing Recruitment Activity Regulation Role Signal Transduction Skeletal system Smooth Muscle Myocytes Solid Stem cells TNFSF11 gene Technology Therapeutic Time Tissues Vascular Smooth Muscle Vascular System Vascular calcification bisphosphonate bone calcification cell type experimental study improved in vivo innovation insight macrophage migration mineralization mouse model multidisciplinary novel osteoclastogenesis osteogenic prevent progenitor public health relevance stem cell biology tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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.