Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification

作者：Yufei Chen, Chenfeng Mao, Rui Gu, Rujia Zhao, Weihao Li, Zihan Ma, Yiting Jia, Fang Yu, Jian Luo, Yi Fu, Jin‐Peng Sun, Wei Kong · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.122.321614 · 被引用次数：44 · 研究领域：Parathyroid Disorders and Treatments、Caveolin-1 and cellular processes、Dermatological and Skeletal Disorders

Background: Vascular calcification is closely related to the all-cause mortality of cardiovascular events. Basement membrane protein nidogen-2 is a key component of the vascular extracellular matrix microenvironment and we recently found it is pivotal for the maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). However, whether nidogen-2 is involved in VSMCs osteochondrogenic transition and vascular calcification remains unclear. Methods: VSMCs was treated with high-phosphate to study VSMC calcification in vitro. Three different mice models (5/6 nephrectomy-induced chronic renal failure, cholecalciferol-overload, and periadventitially administered with CaCl 2 ) were used to study vascular calcification in vivo. Membrane protein interactome, coimmunoprecipitation, flow cytometric binding assay, surface plasmon resonance, G protein signaling, VSMCs calcium assays were performed to clarify the phenotype and elucidate the molecular mechanisms. Results: Nidogen-2 protein levels were significantly reduced in calcified VSMCs and aortas from mice in different vascular calcification model. Nidogen-2 deficiency exacerbated high-phosphate-induced VSMC calcification, whereas the addition of purified nidogen-2 protein markedly alleviated VSMC calcification in vitro. Nidogen-2 -/- mice exhibited aggravated aorta calcification compared to wild-type (WT) mice in response to 5/6 nephrectomy, cholecalciferol-overload, and CaCl 2 administration. Further unbiased coimmun...