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Tie2 is tied at the cell-cell contacts and to extracellular matrix by Angiopoietin-1
Shigetomo Fukuhara,Keisuke Sako,Kazuomi Noda,Kaori Nagao,Koichi Miura,Naoki Mochizuki 생화학분자생물학회 2009 Experimental and molecular medicine Vol.41 No.3
Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo’s group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central. Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo’s group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central.
Zebrafish Vascular Development: General and Tissue-Specific Regulation
Nakajima Hiroyuki,Chiba Ayano,Fukumoto Moe,Morooka Nanami,Mochizuki Naoki 한국지질동맥경화학회 2021 지질·동맥경화학회지 Vol.10 No.2
Circulation is required for the delivery of oxygen and nutrition to tissues and organs, as well as waste collection. Therefore, the heart and vessels develop first during embryogenesis. The circulatory system consists of the heart, blood vessels, and blood cells, which originate from the mesoderm. The gene expression pattern required for blood vessel development is predetermined by the hierarchical and sequential regulation of genes for the differentiation of mesodermal cells. Herein, we review how blood vessels form distinctly in different tissues or organs of zebrafish and how vessel formation is universally or tissue-specifically regulated by signal transduction pathways and blood flow. In addition, the unsolved issues of mutual contacts and interplay of circulatory organs during embryogenesis are discussed.
Vascular Endothelial Cadherin-mediated Cell-cell Adhesion Regulated by a Small GTPase, Rap1
Fukuhra, Shigetomo,Sakurai, Atsuko,Yamagishi, Akiko,Sako, Keisuke,Mochizuki, Naoki Korean Society for Biochemistry and Molecular Biol 2006 Journal of biochemistry and molecular biology Vol.39 No.2
Vascular endothelial cadherin (VE-cadherin), which belongs to the classical cadherin family, is localized at adherens junctions exclusively in vascular endothelial cells. Biochemical and biomechanical cues regulate the VE-cadherin adhesive potential by triggering the intracellular signals. VE-cadherin-mediated cell adhesion is required for cell survival and endothelial cell deadhesion is required for vascular development. It is therefore crucial to understand how VE-cadherin-based cell adhesion is controlled. This review summarizes the inter-endothelial cell adhesions and introduces our recent advance in Rap1-regulated VE-cadherin adhesion. A further analysis of the VE-cadherin recycling system will aid the understanding of cell adhesion/deadhesion mechanisms mediated by VE-cadherin in response to extracellular stimuli during development and angiogenesis.
Lee, Sungwoon,Rho, Seung-Sik,Park, Hyojin,Park, Jeong Ae,Kim, Jihye,Lee, In-Kyu,Koh, Gou Young,Mochizuki, Naoki,Kim, Young-Myeong,Kwon, Young-Guen American Society for Clinical Investigation 2017 The Journal of clinical investigation Vol.127 No.2
<P>Controlled angiogenesis and lymphangiogenesis are essential for tissue development, function, and repair. However, aberrant neovascularization is an essential pathogenic mechanism in many human diseases, including diseases involving tumor growth and survival. Here, we have demonstrated that mice deficient in C-type lectin family 14 member A (CLEC14A) display enhanced angiogenic sprouting and hemorrhage as well as enlarged jugular lymph sacs and lymphatic vessels. CLEC14A formed a complex with VEGFR-3 in endothelial cells (ECs), and CLEC14A KO resulted in a marked reduction in VEGFR-3 that was concomitant with increases in VEGFR-2 expression and downstream signaling. Implanted tumor growth was profoundly reduced in CLEC14A-KO mice compared with that seen in WT littermates, but tumor-bearing CLEC14A-KO mice died sooner. Tumors in CLEC14A-KO mice had increased numbers of nonfunctional blood vessels and severe hemorrhaging. Blockade of VEGFR-2 signaling suppressed these vascular abnormalities and enhanced the survival of tumor-bearing CLEC14A-KO mice. We conclude that CLEC14A acts in vascular homeostasis by fine-tuning VEGFR-2 and VEGFR-3 signaling in ECs, suggesting its relevance in the pathogenesis of angiogenesis-related human disorders.</P>
Kwon, Hyouk-Bum,Fukuhara, Shigetomo,Asakawa, Kazuhide,Ando, Koji,Kashiwada, Takeru,Kawakami, Koichi,Hibi, Masahiko,Kwon, Young-Guen,Kim, Kyu-Won,Alitalo, Kari,Mochizuki, Naoki Company of Biologists 2013 Development Vol.140 No.19
<P>Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in motoneurons resulted in enhanced axon growth of motoneurons over the DA. Both <I>vegfr3</I> morphants and <I>vegfc</I> morphants lost the alignment of motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of motoneuron axons beneath the DA. Finally, a <I>vegfr3</I> mutant fish lacked the motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary motoneurons.</P>