报告题目：Lumen formation in cerebral AVMs
报告人：Yucheng Yao，Ph.D., Professor（Division of Cardiology Department of Medicine David Geffen School of Medicine University of California, Los Angeles）
时间： 2018年12月6日（周四） 10:00-11:30
Research Interests: Dr. Yao’s research focuses on several aspects of cardiovascular diseases, and provides significant insights of vascular diseases. He demonstrated that bone morphogenetic proteins (BMPs) sequentially induced type I receptors, and then activated antagonists to feedback regulate their activity. The pathway has been well recognized to affect the proliferation and differentiation of endothelial cells, and play roles in vascular diseases. He discovered the critical role of endothelial-mesenchymal transitions in vascular calcification, which provides a completely novel mechanism and potential targets for the treatment. Dr. Yao also identified that matrix Gla protein (MGP) constitute a key factor for arteriovenous malformations, and found that excess MGP limited pulmonary AVMs in activin receptor-like kinase 1 (ALK1) deficiency, a genetic disorder known as hereditary hemorrhagic telangiectasia 2.
Recent Representative Publications:
Yao Y, Bennett B, Chen G, Giachelli C, Rosenfeld M, Lusis J, and Boström KI. Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circulation Research. 107:485-494, 2010. PMCID: PMC2994650.
Yao Y*, Jumabay M, Wang A, and Boström KI*. Matrix Gla protein, a novel cause of arteriovenous malformations in mice. Journal of Clinical Investigation. 121:2993-3004, 2011. (* Co-corresponding author.) (On JCI cover) PMCID: PMC3148746.
Yao Y*, Jumabay M, Ly A, Radparvar M, Wang AH, Abdmaulen R, and Boström KI*. (* Co-corresponding author.) Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium. Blood. 119: 5037-5047, 2012. PMCID: PMC3367902.
Yao Y*, Jumabay M, Ly A, Radparvar M, Cubberly MR, and Boström KI*. (* Co-corresponding author.) A role for the endothelium in vascular calcification. Circulation Research. 113:495-504, 2013. PMCID: PMC3851028.
Yao J, Guihard P, Blazquez-Medela AM, Guo Y, Moon JH, Jumabay M, Boström KI, and Yao Y. Serine protease activation essential for endothelial-mesenchymal transition in vascular calcification. Circulation Research. 117:758-769, 2015. (Highlighted by editor and accompanied with editorial) PMCID: PMC4600461.
Yao J, Guihard PJ, Wu X, Blazquez-Medela AM, Spencer MJ, Jumabay M, Tontonoz P, Fogelman AM, Boström KI, and Yao Y. Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. The Journal of Cell Biology. 216:3369-3385, 2017. (Highlighted by editor In Focus) PMCID: PMC5626536
In this study, they report that endothelial-mesenchymal transitions (EndMTs) emerge in the ECs of cerebral arteriovenous malformation (AVMs) and directly cause lumen disorder. They show that excess Sry-box 2 (Sox2) is response for the EndMTs in cerebral AVMs. EC-specific limiting Sox2 normalizes endothelial differentiation and corrects lumen formation to improve cerebral AVMs. Epigenetic studies identify that endothelial jumonji domain-containing protein 5 (JMJD5) is the direct target of Sox2 to induce EndMTs in cerebral ECs. Furthermore, They utilize a high throughput system to identify a chemical compound pronethalol hydrochloride to suppress Sox2 expression. Treatment of pronethalol hydrochloride stabilize endothelial differentiation and lumen formation to reduce cerebral AVMs.