Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells

He, Jinlong; Bao, Qiankun; Zhang, Yan; Liu, Mingming; Lv, Huizhen; Liu, Yajin; Liu, Yao; Li, Bochuan; Zhang, Chenghu; He, Shuang; Zhai, Guijin; Zhu, Yan; Liu, Xin; Zhang, Kai; Wang, Xiu‐Jie; Zou, Ming‐Hui; Zhu, Yi; Ai, Ding

doi:10.1161/circresaha.117.311950

Cited by 109 publications

(109 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…YAP nuclear localization was impaired in the angiogenic front of Lpa4;Lpa6 iΔEC retinas. Several independent studies have revealed that endothelial YAP/TAZ mediate sprouting angiogenesis (31)(32)(33)(34)(35)(36). In this context, we propose LPA4 and LPA6 as regulators of sprouting angiogenesis that repress DLL4 expression by activating YAP/TAZ in ECs.…”

Section: Discussionmentioning

confidence: 64%

See 1 more Smart Citation

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Yasuda

Kobayashi

Akahoshi

et al. 2019

Journal of Clinical Investigation

View full text Add to dashboard Cite

al cooperation between LPA4 and LPA6 is essential for embryonic development. Since Lpa4;Lpa5-DKO and Lpa5;Lpa6-DKO mice were born at the expected Mendelian ratios and had no obvious abnormalities (Supplemental Tables 4 and 5), LPA5 is unlikely to be involved in embryonic development. To examine the roles of LPA4 and LPA6 in embryonic development, yolk sac and embryo proper were observed at various stages of gestation. At E8.5, both Lpa4;Lpa6-DKO yolk sac and embryo proper appeared normal (Supplemental Figure 1, A and B). However, at E9.5-10.5, almost all of Lpa4;Lpa6-DKO embryos proper had various morphological abnormalities, such as severe pericardial effusion (Figure 1A and Supplemental Figure 1, B-D), axial turning abnormality (Supplemental Figure 1, B, E, and F), and developmental delay (Figure 1, A and B, and Supplemental Figure 1, B, G, and H). DKO yolk sacs lacked large blood vessels at E9.5-10.5, whereas WT yolk sacs had well-developed blood vessels (Figure 1B and Supplemental Figure 1, A, I, and J). We observed that all DKO embryos died by E11.5 (Supplemental Figure 1, B, K, and L, and Supplemental Table 6). Histological analysis showed that the endoderm and mesoderm of the yolk sacs were more widely separated in the DKO tissue (Figure 1C). Despite this vascular defect, erythrocytes were present in Lpa4;Lpa6-DKO yolk sacs (Figure 1C). Blood vessel-stained whole-mount embryos at E10.5 revealed that DKO embryos had enlarged dorsal aortae and poor vascular networks in the head and intersomitic regions, compared with WT embryos (Figure 1D). Furthermore, blood vessel-stained cross sections of embryos at E9.5 also revealed that DKO embryos had enlarged dorsal aortae and thinned neural tubes, compared with WT embryos (Figure 1E). These results strongly suggest that both LPA4 and LPA6 are indispensable for embryonic angiogenesis. Endothelial LPA4 and LPA6 are involved in retinal angiogenesis. Previously, we detected mRNA expression of Lpa4 and LPA6 in vascular ECs (8, 16). To investigate the functional roles of endothelial LPA4 and LPA6, we generated a tamoxifen-inducible and EC-specific Lpa4/Lpa6 deletion mouse line by crossing Lpa4;Lpa6 double-floxed mutants with transgenic mice carrying Cdh5-CreER T2 (ref. 37, Figure 2A, and Supplemental Figure 2A). The resulting Lpa4 fl/fl(Y) Lpa6 fl/fl Cdh5-CreER T2 mice (termed hereafter Lpa4; Lpa6 iΔEC) were treated with tamoxifen from P1 to P3. Allele-specific PCR confirmed recombination of both floxed alleles in the tails of Lpa4;Lpa6 iΔEC mice at P5 (Supplemental Figure 2B). At P5, we found that the radial expansion, EC area, and retinal blood vessel branching were significantly reduced in Lpa4;Lpa6 iΔEC mice compared with those in control CreER T2-negative Lpa4 fl/fl(Y) ;Lpa6 fl/fl littermates (Figure 2, C and F-H). At the angiogenic front, sprouts of retinal vessels were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, D and I). Additionally, both the number and length of sprouting filopodia were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, E, J...

show abstract

Section: Discussionmentioning

confidence: 64%

“…A previous report showed that LPA-induced Gα12/Gα13 signaling activated YAP in HEK293 cells (30). Recently, several independent studies revealed that endothelial YAP/TAZ mediate sprouting angiogenesis (31)(32)(33)(34)(35)(36). However, the biological significance of GPCR-induced YAP/TAZ activation is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Yasuda

Kobayashi

Akahoshi

et al. 2019

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…Alternatively, the reduction in H3K27ac marks on NOS3 enhancers may alter its response in PAH. Third, YAP1 promotes angiogenesis in endothelial cells 28 but YAP1 is not known to be regulated by TGFβ in endothelial cells 29 . Here too the impaired upregulation of YAP1 as well as NOS3 in response to TGFβ in PAH PAEC might underlie the impaired angiogenesis in these cells.…”

Section: Extensive Remodeling Of H3k27ac In Pah Patients Vs Controlsmentioning

confidence: 99%

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

Reyes-Palomares

Grubert

et al. 2020

Nat Commun

View full text Add to dashboard Cite

Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymaltransition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.

show abstract

“…In addition, phosphorylation of YAP at Y 357 increases its stability and in turn upregulates its activity (9). Recently, YAP was identified to be crucial in ECs in different biological processes, including angiogenesis (10) and atherosclerosis (11,12). Moreover, the suppression of YAP in response to LSS plays an important role in maintaining vessel homeostasis in ECs (11,12).…”

Section: Introductionmentioning

confidence: 99%

c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

Li¹,

He²,

Lv³

et al. 2019

Journal of Clinical Investigation

Self Cite

102

106

View full text Add to dashboard Cite

Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells

Abstract: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.

Cited by 109 publications

References 65 publications

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

Contact Info

Product

Resources

About