BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway

Yongyun Li; Qingfeng Shang; Peng Li; Zhi Yang; Jie Yang; Jiahao Shi; Shengfang Ge; Yefei Wang; Xianqun Fan; Renbing Jia

doi:10.1016/j.yjmcc.2020.07.010

BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway

J Mol Cell Cardiol. 2020 Oct:147:92-107. doi: 10.1016/j.yjmcc.2020.07.010. Epub 2020 Jul 28.

Authors

Yongyun Li¹, Qingfeng Shang², Peng Li³, Zhi Yang⁴, Jie Yang⁵, Jiahao Shi⁶, Shengfang Ge⁷, Yefei Wang⁸, Xianqun Fan⁹, Renbing Jia¹⁰

Affiliations

¹ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: liyongyun@sjtu.edu.cn.
² Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: sqf123@sjtu.edu.cn.
³ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: hubeilipeng@163.com.
⁴ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: yangzhi@sibs.ac.cn.
⁵ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: joeyyang2824@yahoo.com.
⁶ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: 1176914935@qq.com.
⁷ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: geshengfang@sjtu.edu.cn.
⁸ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: paper34@163.com.
⁹ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: fanxq@sjtu.edu.cn.
¹⁰ Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. Electronic address: renbingjia@sjtu.edu.cn.

PMID: 32730768
DOI: 10.1016/j.yjmcc.2020.07.010

Abstract

Venous malformation (VM) is a type of vascular morphogenic defect in humans with an incidence of 1%. Although gene mutation is considered as the most common cause of VM, the pathogenesis of those without gene mutation remains to be elucidated. Here, we aimed to explore the relation of bone morphogenetic protein 9 (BMP9) and development of VM. At first, we found serum and tissue BMP9 expression in VM patients was significantly lower than that in healthy subjects, detected via enzyme-linked immunosorbent assay. Next, with wound healing assay, transwell assay and tube formation assay, we discovered BMP9 could inhibit migration and enhance tube formation activity of human umbilical vein endothelial cells (HUVECs) via receptor activin receptor-like kinase 1 (ALK1). Besides, BMP9 improved the expression of structural proteins alpha-smooth muscle actin (α-SMA) and Desmin in human umbilical vein smooth muscle cells (HUVSMCs) via activation of the SMAD1/5-ID1 pathway, determined by RNA-based next-generation sequencing, qPCR, immunofluorescence and western blotting. Intriguingly, this effect could be blocked by receptor ALK1 inhibitor, SMAD1/5 inhibitor and siRNAs targeting ID1, verifying the BMP9/ALK1/SMAD1/5/ID1/α-SMA pathway. Meanwhile, knocking out BMP9 in C57BL/6 mice embryo led to α-SMA scarcity in walls of lung and mesenteric vessels, as well as walls of small trachea. BMP9-/- zebrafish also exhibited abnormal vascular maturity, indicating a critical role of BMP9 in vascular maturity and remodeling. Finally, a VM mice model revealed that BMP9 might have therapeutic effect in VM progression. Our study discovered that BMP9 might inhibit the occurrence of VM by strengthening the vessel wall and maintaining endothelium quiescence. These findings provide promising evidences of new therapeutic targets that might be used for the management of VM.

Keywords: Alpha-smooth muscle actin; Bone morphogenetic protein 9; Orbital venous malformation; Vascular remodeling; Venous malformation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism*
Adolescent
Adult
Aged
Animals
Cell Movement
Cell Proliferation
Child
Child, Preschool
Disease Models, Animal
Down-Regulation
Female
Growth Differentiation Factor 2 / metabolism*
Human Umbilical Vein Endothelial Cells / pathology*
Humans
Inhibitor of Differentiation Protein 1 / metabolism*
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / metabolism
Neovascularization, Physiologic
Signal Transduction*
Smad1 Protein / metabolism*
Smad5 Protein / metabolism*
Transforming Growth Factor beta / metabolism
Veins / abnormalities*
Veins / pathology
Young Adult

Substances

ACTA2 protein, human
Actins
Growth Differentiation Factor 2
Inhibitor of Differentiation Protein 1
Smad1 Protein
Smad5 Protein
Transforming Growth Factor beta