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Reciprocal Notch‐Jagged Signaling Regulates Angiogenic Endothelial Cell Phenotype
Author(s) -
Hughes Chris,
Sainson Richard C. A.,
Conn Erin M.,
Chu Henry C.,
Brown Julie,
Aoto Jason N.,
Nakatsu Martin N.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a440
Subject(s) - notch signaling pathway , microbiology and biotechnology , sprouting angiogenesis , hes3 signaling axis , angiogenesis , notch proteins , phenotype , biology , filopodia , lamellipodium , pdz domain , signal transduction , rac1 , cell migration , cell , actin , genetics , neovascularization , gene
Angiogenesis involves the interplay between endothelial cells (EC) of very distinct phenotype. A newly developing sprout is led by a tip cell that rarely divides, but is highly motile and extends numerous filopodia and lamellipodia into the surrounding matrix. Behind the tip cell are trunk cells, which divide and rearrange to form intercellular lumens. As the vessel matures branching occurs and later still anastomoses form. Each of these processes also involves EC of distinct phenotype, however very little is known about how these different phenotypes are initiated and maintained. Using an in vitro angiogenesis assay that models all of these phenotypes, we find that jagged‐notch signaling regulates the trunk and tip cell phenotypes. During vessel maturation signaling from jagged through notch (modeled by intracellular notch – notchIC) upregulates the transcription factor HESR1, downregulates VEGFR2 and suppresses sprouting. Conversely, “reverse signaling” from notch to jagged (modeled by intracellular jagged – jaggedIC) suppresses notch signaling, induces sprouting and upregulates VEGFR2 and MMP2 expression. JaggedIC suppression of notch signaling does not involve blocking nuclear localization of notchIC, and is independent of effects on notch cleavage. Suppression requires both the NLS and the PDZ‐ligand domain of jagged. Finally, microarray experiments suggest that signaling by jagged‐IC induces a suite of genes consistent with a tip cell phenotype. Thus, bidirectional jagged‐notch signaling regulates EC phenotype during angiogenic sprouting. This work was supported by NIH RO1 HL60067