Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells

Huang, Yao-Qi; Li, Jianjun; Hu, Liang; Lee, Merlin; Karpatkin, Simon

doi:10.1182/blood.v99.5.1646

Cited by 124 publications

(99 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, the secretion of ANG-2 stored in Weibel-Palade bodies of ECs is also tightly regulated 37 . Indeed, thrombin increased both ANG-2 synthesis in ECs and its secretion 38 . However, how ANG-2 is regulated in ECs was not clearly understood, although ANG-2 has been identified as a transcriptional target gene of FOXO1 in ECs 31,39 .…”

Section: Discussionmentioning

confidence: 98%

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

View full text Add to dashboard Cite

Angiogenesis is regulated by the dynamic interaction between endothelial cells (ECs).Hippo-Yes-associated protein (YAP) signalling has emerged as a key pathway that controls organ size and tissue growth by mediating cell contact inhibition. However, the role of YAP in EC has not been defined yet. Here, we show expression of YAP in the developing front of mouse retinal vessels. YAP subcellular localization, phosphorylation and activity are regulated by VE-cadherin-mediated-EC contacts. This VE-cadherin-dependent YAP phosphorylation requires phosphoinositide 3-kinase-Akt activation. We further identify angiopoietin-2 (ANG-2) as a potential transcriptional target of YAP in regulating angiogenic activity of EC in vitro and in vivo. Overexpression of YAP-active form in EC enhances angiogenic sprouting, and this effect is blocked by ANG-2 depletion or soluble Tie-2 treatment. These findings implicate YAP as a critical regulator in angiogenesis and provide new insights into the mechanism coordinating junctional stability and angiogenic activation of ECs.

show abstract

Section: Discussionmentioning

confidence: 98%

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that vascular endothelial cells are the primary source of Ang2 (32)(33)(34)(35). High glucose increases Ang2 mRNA in HRMECs (36).…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

et al. 2014

View full text Add to dashboard Cite

Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR.

show abstract

“…Expression profiling studies have identified endothelial cells as the primary source of Ang-2 and a dramatic transcriptional regulation of Ang-2 production upon endothelial-cell activation (Gale et al, 2002;Hackett et al, 2000;Holash et al, 1999;Huang et al, 2002;Mandriota and Pepper, 1998;Stratmann et al, 1998;Zhang et al, 2003). Correspondingly, the Ang-2 promoter contains unique positive and negative regulatory elements that control endothelial cell expression of Ang-2 .…”

mentioning

confidence: 99%

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

Scharpfenecker¹,

Fiedler²,

Reiss³

et al. 2005

Journal of Cell Science

339

260

View full text Add to dashboard Cite

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the endothelial receptor tyrosine kinase Tie-2, which controls vascular assembly and endothelial quiescence. The largely complementary phenotypes of Ang-1-deficient mice and Ang-2-overexpressing mice have led to an antagonistic model in which Ang-1 acts as Tie-2-activating agonist and Ang-2 acts as a Tie-2-inhibiting antagonist. To date, no mechanistic equivalent of the antagonistic Ang-1/Ang-2 model has been established and the mechanisms of Ang-2 function in particular remain mysterious. We have studied the effector functions of Ang-1 and Ang-2 on quiescent endothelial cells using a three-dimensional co-culture model of endothelial cells and smooth-muscle cells. Endothelial-cell monolayer integrity in this model is dependent on Tie-2 signaling, as evidenced by detaching endothelial cells following exposure to the small molecular weight Tie-2 inhibitor A-422885.66, which cannot be overcome by exogenous Ang-1. Accordingly, exogenous Ang-2 rapidly destabilizes the endothelial layer, which can be observed within 30-60 minutes and leads to prominent endothelial-cell detachment within 4 hours. Exogenous Ang-2-mediated endothelial-cell detachment can be rescued by Ang-1, soluble Tie-2 and vascular endothelial growth factor. Similar findings were obtained in an umbilical-vein explant model. Ang-2 is mainly produced by endothelial cells and therefore acts primarily in an autocrine manner. Thus, stimulated release of endogenous Ang-2 or overexpression of Ang-2 in endothelial cells perturbs co-culture spheroid integrity, which can be rescued by exogenous Ang-1 and vascular endothelial growth factor. However, autocrine Ang-2-mediated endothelial-cell detachment cannot be blocked by soluble Tie-2. Taken together, the data demonstrate for the first time the antagonistic Ang-1/Ang-2 concept in a defined cellular model and identify Ang-2 as a rapidly acting autocrine regulator of the endothelium that acts through an internal autocrine loop mechanism.

show abstract

Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells

Cited by 124 publications

References 45 publications

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

Contact Info

Product

Resources

About