Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) and Notch signaling are emerging as essential regulators of the vasculature, and important in disorders such as arteriovenous malformations (AVMs). Our previous studies have demonstrated that excess BMP induces Notch signaling causing cerebral AVMs. In preliminary studies, we demonstrate a strong endothelial induction of Sox2 in human cerebral AVMs, and a dramatic improvement of cerebral AVMs after limiting Sox2 in ECs. We find that excess transcriptional activity of Sox2 disrupts cerebral EC differentiation to cause lumen disorder in AVMs. Sox2 is regulated by crosstalk of BMP and Notch signaling. In vitro, we show that BMP-induced Notch ligands Jagged 1 and 2 upregulate Sox2, and knockdown of Notch1 receptor diminishes Sox2 induction. In vivo, Jagged 1 and 2 and Notch1 are increased and directly targeted Sox2 in MGP-deficient cerebral ECs, in which a decrease of Jagged 1 or 2 reduces Sox2 expression. In contrast, we find no induction or significant changes of transcriptional effects of Sox2 in pulmonary AVMs, where instead the expression of VEGF is increased. Limiting endothelial Sox2 does not improve pulmonary AVMs. To induce Sox2, Notch requires ski-interacting protein (Skip), which is active in brain ECs but inactive in pulmonary ECs. Furthermore, we have created a high throughput-screening model and aim to identify chemical compounds that suppress Sox2 expression in brain ECs. We hypothesize that regulation of Sox2 and its transcriptional activity is important in the maintenance of EC differentiation and lumen formation in normal cerebral vasculature.
Specific Aim 1 will determine how Sox2 is regulated by BMP and Notch signaling and affects the differentiation of brain endothelial cells.
Specific Aim 2 will determine if Sox2 is induced to contribute to human cerebral AVMs.
Specific Aim 3 will determine how regulation of Sox2 differs in cerebral versus pulmonary AVMs and identify the chemical compounds that suppress Sox2 expression. If successful, the obtained information may translate into strategies for using Sox2 inhibitors in the treatment of cerebral AVMs. The study may also provide significant insights of tissue-specific formation of AVMs, and lead to different treatment strategies for AVMs.
Our studies are relevant to the diagnosis and treatment of diseased vessels in the brain, so-called cerebral arteriovenous malformation. This study focuses on factors referred to sex determining region Y-box 2, Notch and bone morphogenetic proteins, and how they communicate with each other to regulate the formation of the vessel lumen and the vessel lining. Understanding how these factors work may lead to new strategies for prevention and treatment of arteriovenous malformation.
| Boström, Kristina I; Yao, Jiayi; Wu, Xiuju et al. (2018) Endothelial Cells May Have Tissue-Specific Origins. J Cell Biol Histol 1: |
| Jumabay, Medet; Zhumabai, Jiayinaguli; Mansurov, Nurlan et al. (2018) Combined effects of bone morphogenetic protein 10 and crossveinless-2 on cardiomyocyte differentiation in mouse adipocyte-derived stem cells. J Cell Physiol 233:1812-1822 |
| Yao, Jiayi; Guihard, Pierre J; Wu, Xiuju et al. (2017) Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. J Cell Biol 216:3369-3385 |
| Guihard, Pierre J; Yao, Jiayi; Blazquez-Medela, Ana M et al. (2016) Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice. PLoS One 11:e0167936 |
| Boström, Kristina I; Yao, Jiayi; Guihard, Pierre J et al. (2016) Endothelial-mesenchymal transition in atherosclerotic lesion calcification. Atherosclerosis 253:124-127 |
| Yao, Jiayi; Guihard, Pierre J; Blazquez-Medela, Ana M et al. (2016) Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells. Angiogenesis 19:1-7 |
| Boström, Kristina I; Guihard, Pierre; Blazquez Medela, Ana M et al. (2015) Matrix Gla protein limits pulmonary arteriovenous malformations in ALK1 deficiency. Eur Respir J 45:849-52 |
| Blazquez-Medela, Ana M; Guihard, Pierre J; Yao, Jiayi et al. (2015) ABCC6 deficiency is associated with activation of BMP signaling in liver and kidney. FEBS Open Bio 5:257-63 |
| Yao, Jiayi; Guihard, Pierre J; Blazquez-Medela, Ana M et al. (2015) Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification. Circ Res 117:758-69 |
| Jumabay, Medet; Abdmaulen, Raushan; Ly, Albert et al. (2014) Pluripotent stem cells derived from mouse and human white mature adipocytes. Stem Cells Transl Med 3:161-71 |
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