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Nakaoka, Yoshikazu,Nishida, Keigo,Narimatsu, Masahiro,Kamiya, Atsunori,Minami, Takashi,Sawa, Hirofumi,Okawa, Katsuya,Fujio, Yasushi,Koyama, Tatsuya,Maeda, Makiko,Sone, Manami,Yamasaki, Satoru,Arai, Yu American Society for Clinical Investigation 2007 The Journal of clinical investigation Vol.117 No.7
Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity.
Park, Dae-Young,Lee, Junyeop,Park, Intae,Choi, Dongwon,Lee, Sunju,Song, Sukhyun,Hwang, Yoonha,Hong, Ki Yong,Nakaoka, Yoshikazu,Makinen, Taija,Kim, Pilhan,Alitalo, Kari,Hong, Young-Kwon,Koh, Gou Young American Society for Clinical Investigation 2014 The Journal of clinical investigation Vol.124 No.9
<P>Schlemm's canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin α9 and exhibited continuous vascular endothelial-cadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity.</P>
Park, Ho Seon,Kim, Hak Zoo,Park, Jong Suk,Lee, Junyeop,Lee, Seung-Pyo,Kim, Hail,Ahn, Chul Woo,Nakaoka, Yoshikazu,Koh, Gou Young,Kang, Shinae American Diabetes Association 2019 Diabetes Vol. No.
<P>Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a well-known angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1<SUP>sys−/−</SUP>) and β-cell–specific Ang1 knockout (Ang1<SUP>β-cell−/−</SUP>) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1<SUP>sys−/−</SUP> and Ang1<SUP>sys+/+</SUP> mice, serum insulin levels were lower in Ang1<SUP>sys−/−</SUP> mice, resulting in significant glucose intolerance. Similar results were observed in Ang1<SUP>β-cell−/−</SUP> mice, suggesting a critical role of β-cell–derived Ang1 in glucose homeostasis. There were no differences in β-cell area or vasculature density, but glucose-stimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1<SUP>β-cell−/−</SUP> compared with Ang1<SUP>β-cell+/+</SUP> mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1<SUP>β-cell−/−</SUP> mice. In conclusion, β-cell–derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.</P>