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UXT potentiates angiogenesis by attenuating Notch signaling.

ABSTRACT: Angiogenesis is spatially and temporally orchestrated by a myriad of signaling pathways, including the Notch signaling pathway. Here, we identified UXT as an evolutionarily conserved and developmentally expressed protein, indispensable for intersegmental vessel (ISV) formation in zebrafish. Deficiency of UXT in zebrafish embryos results in shorter ISVs, loss of tip cell behavior, and impairment of endothelial cell migration and division. Significantly, UXT attenuates the expression of the Notch-responsive genes in vitro and in vivo. Mechanistically, UXT binds to the promoters of the Notch signaling target genes and specifically interacts with the transactivation region domain of the Notch intracellular domain (NICD), impairing the interaction between NICD and the transcription factor RBP-J? endogenously. This prevents RBP-J?/CSL from activation and thus inhibits the consequent gene inductions. Furthermore, blockade of Notch signaling rescues the angiogenesis defect caused by UXT knockdown both in vitro and in vivo. Taken together, the data presented in this study characterize UXT as a novel repressor of Notch signaling, shedding new light on the molecular regulation of angiogenesis.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC4325377 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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UXT potentiates angiogenesis by attenuating Notch signaling.

Zhou Yi Y Ge Rui R Wang Rui R Liu Feng F Huang Yuefeng Y Liu Heng H Hao Yan Y Zhou Qin Q Wang Chen C

Development (Cambridge, England) 20150123 4

Angiogenesis is spatially and temporally orchestrated by a myriad of signaling pathways, including the Notch signaling pathway. Here, we identified UXT as an evolutionarily conserved and developmentally expressed protein, indispensable for intersegmental vessel (ISV) formation in zebrafish. Deficiency of UXT in zebrafish embryos results in shorter ISVs, loss of tip cell behavior, and impairment of endothelial cell migration and division. Significantly, UXT attenuates the expression of the Notch- ...[more]

PMID: 25617435

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Project description:RATIONALE:The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. OBJECTIVE:The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. METHODS AND RESULTS:Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. CONCLUSIONS:These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.

Project description:RationaleAngiogenesis improves perfusion to the ischemic tissue after acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that AIBP (apolipoprotein A-I [apoA-I]-binding protein)-regulated cholesterol efflux in endothelial cells controls zebra fish embryonic angiogenesis.ObjectiveThis study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions and to explore the underlying molecular mechanism.Methods and resultsIn this article, we report the generation of AIBP knockout (Apoa1bp-/-) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to nonlipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4 (delta-like ligand 4)-stimulated Notch activation in human retinal endothelial cells. Increasing high-density lipoprotein levels in Apoa1bp-/- mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp-/- mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp-/- mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy.ConclusionsOur data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions.

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UXT potentiates angiogenesis by attenuating Notch signaling.

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UXT potentiates angiogenesis by attenuating Notch signaling.

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