105 research outputs found
The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination
Cell-to-cell junctions are critical for the formation of endothelial barriers, and its disorganization is required for sprouting angiogenesis. Members of the angiomotin (AMOT) family have emerged as key regulators in the control of endothelial cell (EC) junction stability and permeability. However, the underlying mechanism by which the AMOT family is regulated in ECs remains unclear. Here we report that HECW2, a novel EC ubiquitin E3 ligase, plays a critical role in stabilizing endothelial cell-to-cell junctions by regulating AMOT-like 1 (AMOTL1) stability. HECW2 physically interacts with AMOTL1 and enhances its stability via lysine 63-linked ubiquitination. HECW2 depletion in human ECs decreases AMOTL1 stability, loosening the cell-to-cell junctions and altering subcellular localization of yes-associated protein (YAP) from cytoplasm into the nucleus. Knockdown of HECW2 also results in increased angiogenic sprouting, and this effect is blocked by depletion of ANG-2, a potential target of YAP. These results demonstrate that HECW2 is a novel regulator of angiogenesis and provide new insights into the mechanisms coordinating junction stability and angiogenic activation in ECs.ope
Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice.
Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis.ope
Roles of YAP in mediating endothelial cell junctional stability and vascular remodeling
Angiogenesis is a complex process involving dynamic interaction of various cell to cell interactions. Endothelial cell interactions regulated by growth factors, inflammatory cytokines, or hemodynamic stress are critical for balancing vascular quiescence and activation. Yes-associated protein (YAP), an effector of Hippo signaling, is known to play significant roles in maintaining cellular homeostasis. However, its role in endothelial cells for angiogenic regulation remains relatively unexplored. We demonstrated the critical role of YAP in vascular endothelial cells and elucidated the underlying molecular mechanisms involved in angiogenic regulation of YAP. YAP was expressed in active angiogenic regions where endothelial cell junctions were relatively loosened. Consistently, YAP subcellular localization and activity were regulated by VE-cadherin-mediated PI3K/Akt pathway. YAP thereby regulated endothelial sprouting via angiopoietin-2 expression. These results provide an insight into a model of coordinating endothelial junctional stability and angiogenic activation through YAP.ope
LDB2 regulates the expression of DLL4 through the formation of oligomeric complexes in endothelial cells
Delta-like ligand 4 (DLL4) expression in endothelial cells is intimately associated with angiogenic sprouting and vascular remodeling, but the precise mechanism of transcriptional regulation of DLL4 remains incompletely understood. Here, we showed that LIM-domain binding protein 2 (LDB2) plays an important role in regulating basal DLL4 and VEGF-induced DLL4 expression. Knockdown of LDB2 using siRNA enhanced endothelial sprouting and tubular network formation in vitro. Injection of ldb2-morpholino resulted in defective development of intersegmental vessels in zebrafish. Reduction or overexpression of LDB2 in endothelial cells decreased or increased DLL4 expression. LDB2 regulated DLL4 promoter activity by binding to its promoter region and the same promoter region was occupied and regulated by the LMO2/TAL1/GATA2 complex. Interestingly, LDB2 also mediated VEGF-induced DLL4 expression in endothelial cells. The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.ope
Increased Thrombogenicity in Chronic Renal Failure in a Rat Model Induced by 5/6 Ablation/Infarction.
PURPOSE: Abnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function.
MATERIALS AND METHODS: CRF was induced by 5/6 ablation/infarction of the kidneys in Sprague-Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeClโ)-induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry.
RESULTS: FeClโ-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2ยฑ1.1 sec vs. 17.8ยฑ1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2ยฑ201.1 ฮผm vs. 114.0ยฑ145.1 ฮผm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0ยฑ7.3 sec vs. 72.8ยฑ5.0 sec, p=0.032) and increased clot growth kinetics (ฮฑ angle, 84.8ยฑ0.2ยฐ vs. 82.0ยฑ0.6ยฐ, p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2ยฑ0.2% vs. 44.6ยฑ1.2%, p=0.006).
CONCLUSION: Our study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF.ope
TNF-ฮฑ-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells
YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-ฮฑ. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-ฮฑ in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-ฮฑ-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-ฮฑ. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-ฮฑ-induced NF-ฮบB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-ฮฑ-induced endothelial cell adhesive properties without affecting the NF-ฮบB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.ope
Focusing on the Russian perspective
ํ์๋
ผ๋ฌธ (์์ฌ)-- ์์ธ๋ํ๊ต ๋ํ์ : ๊ตญ์ ๋ํ์ ๊ตญ์ ํ๊ณผ(๊ตญ์ ํ๋ ฅ์ ๊ณต), 2019. 2. ์ ์ฑํธ.์ค๊ตญ๊ณผ ๋ฌ์์์ ๊ด๊ณ๋ ํ๋ ฅ๊ณผ ๊ฒฝ์์ด ํญ์ ์กด์ฌํด์๋ค. ๋ฌ์์๋ ์ต๊ทผ ์์์๋ก ๋์ ๋๋ฆฌ๋ฉด์ ์ ๋๋ฐฉ์ ์ฑ
๊ณผ ํจ๊ป ๊ทน๋์ง์ญ์์์ ์ ์น์ , ๊ฒฝ์ ์ ์
์ง๋ฅผ ๊ฐํํ๊ณ ์๋ค. ์ด์ ๋ฐ๋ผ ์ค๊ตญ๊ณผ์ ๊ด๊ณ๋ ๋ฐ์ ๋ ๊ฑฐ๋ผ ์์ํ์์ง๋ง ์ค์ง์ ์ธ ํ๋ ฅ์ ์ง์ ์ด ๋ณด์ด์ง ์๊ณ ์๋ค. ๋ณธ ๋
ผ๋ฌธ์ ์ด๋ฅผ ๋ฌ์์ ๊ทน๋์ง์ญ(์ง์ญ์ฐจ์)๊ณผ ์๋ฃจ๋น๋
ธ ํญ๋ง ๊ฐ๋ฐํ๋ก์ ํธ(์์ง์ญ ์ฐจ์)๋ก ๊ตฌ๋ถํ์ฌ ๋ ๊ตญ๊ฐ๊ฐ ํ๋ ฅ์ด ์ง์ฒด๋๋ ์์ธ์ ๋ฌ์์์ ์
์ฅ์์ ๋ถ์ํ์๋ค. ์ฐ์ ์ง์ญ์ฐจ์์ ๊ทน๋์ง์ญ์์ ๋ฌ์์๊ฐ ์ค๊ตญ๊ณผ ๋์น์ ์ด์ ๋ก๋ 1) ์ค๊ตญ์ ์ด์ฉํ ๋ฏธ๊ตญ์ ์์์ ํ๊ท์ ์ฑ
(Pivot to Asia)์ ๋ํ ๊ฒฌ์ ์ ์ด์ ๋ฐ๋ฅธ ์๊ตญ์ ๊ฐ๋๊ตญ ์
์ง ์ฌํ๋ณด์ 2) ์์์ ํํ์ ์ง์ญ์์์ ์ค๊ตญ ๋ถ์ ์ฐ๋ ค๊ฐ ์๋ค. ์์ง์ญ ์ฐจ์์ ์๋ฃจ๋น๋
ธ ํญ๋ง ๊ฐ๋ฐ์์ ๋ฌ์์๋ 1) ์ ๊ฒฝ์ง์ญ์์์ ์ค๊ตญ ์ฐ์ธ ์ฐ๋ ค์ 2) ์ด ์ง์ญ๊ฐ๋ฐ์ ๋ํ ๋ฎ์ ์์ค์ ์ฑ
์๊ฐ์ ์๋ค.
๊ทน๋์ง์ญ์์ ๋ฌ์์๋ ๊ตญ์ ์์คํ
์ ๋ฏธ๊ตญ์ ๋ํ ๊ฒฌ์ ์ ๊ท ํ, ์ง์ญ์ ์์ค์์์ ์ค๊ตญ์ ๋ํ ์ํ๋ถ์ฐ(hedging)์ ๋ ๊ฐ์ง ๋จ๊ณ๊ฐ ๊ด์ฐฐ๋์ด์ง๋ค. ์ง์ญ์ ๋ฐ ์์ง์ญ์ ์ฐจ์์์ ๋ฌ์์๋ ์ค๊ตญ๊ณผ์ ๊ด๊ณ์ ์์ด ๊ฒฝ์ ์ ์ธ ์ธก๋ฉด๋ณด๋ค๋ ์๊ตญ์ ์๋ณด๋ฅผ ๋ ์ค์ํ๊ณ ์๋ค. ๊ทธ ๊ฒฐ๊ณผ ํ์ฌ ๋ฌ์์๋ ๋ค๋ฅธ ์ฃผ์ ๋์์์ ๊ตญ๊ฐ๋ค์ ์ฐธ์ฌ๋ฅผ ์ ๋ํ๋ ๋ฑ ํฌ์์ ๋ค์ํ๋ฅผ ํ๋ ๋
ธ๋ ฅ์ ํ๊ณ ์๋ค. ํ๊ตญ์ ๊ทน๋์ง์ญ์์์ ๊ฐ๋ฐ์ฐธ์ฌ๋ฅผ ํตํด ๋์์์์ ๋ํ ์ํฅ๋ ฅ์ ๊ฐํํ๊ณ ์ถํ์ ๋ถํ๊ณผ ๋ฌ์์๊ฐ 3๊ตญ ๊ฒฝ์ ํ๋ ฅ์ ๋์ฐธํ ์ ์๋ ๊ธฐํ๊ฐ ์๊ธฐ ๋๋ฌธ์ ์ ๊ทน์ ์ผ๋ก ๊ฐ๋ฐ์ฐธ์ฌ๋ฅผ ๋ชจ์ํ ํ์๊ฐ ์๋ค.Cooperation and Competition simultaneously existed in the Sino-Russian relations. As Russia turned its attention to Asia and prioritized the Turn to the East policy and tried to increase its political influence and economic presence in the Russian Far East (RFE), Sino-Russian economic relations were expected to develop. However, cooperation was not showing much progress. This paper analyzed the hindrance factors from the Russian perspective by dividing in to two approaches: RFE (Regional level) and Zarubino Port Development project (Sub-regional level). In the RFE, the main hindrance factors were 1) Balancing US pivot to Asia and resurging their status of super power, 2) Wary of China's emergence in the Asia Pacific region. In the Sino-Russian border areas, the hindrance factors were 1) Wary of China's domination in the Sino- Russian border areas, 2) Low commitment to develop the border areas.
In the China-Russia relations, we can observe two levels: Balancing against US on the international system and hedging to one another to its regional level. Both regional and sub-regional level approach show Russia is more concerned to security rather than economic cooperation when dealing with China in the RFE. Accordingly, Russia is trying to diversify its source of investment by inviting other main North East Asian (NEA) countries. For Korea, this is an opportunity to improve its influence in NEA and later attract North Korea(NK) to participate in the trilateral economic cooperation between two Koreas and Russia. Therefore, it is important to consider participating the RFE development, if conditions allow.I. Introduction 1
1. Research Purpose and Significance 2
2. Research Design 4
2-1. Literature Review 4
2-2. Research Question 8
2-3. Research Outline 9
II. China- Russia Relationship in the Russian Far East (RFE) 11
1. Strategic Value and Regional Development of Russia Far East 11
2. Strategic Partnership between China and Russia 18
3. China- Russia Interactions in the RFE 21
3-1. Hindrance Factors 25
3-1-1. Balancing US pivot to Asia 25
3-1-2. Wary of China's emergence in the Asia Pacific region 27
4. Assessment of Russias position in RFE 30
III. Cross-border cooperation in the Russian Far East (RFE) 31
1. Construction of transport network in the Sino-Russian border areas 31
2. China - Russia interactions in the Sino- Russian border areas 32
3. Sino - Russian cooperative project: Zarubino Port Development Project 37
3-1. Hindrance Factors 43
3-1-1. Wary of China's dominance in the Sino - Russian border areas 43
3-1-2. Low Commitment to develop the border areas 46
4. Assessment of Russias position in border areas 47
IV. Implications for Korea and the Regional cooperation in NEA 49
1. Regional cooperation in North East Asia 49
2. Implication for Korea 52
V. Conclusion 55
VI. Reference 59
VII. Abstract in Korean 77Maste
EJC์์์ Aly์ ์ญํ ๊ณผ Y14๊ณผ์ ์ํธ์์ฉ์ ๊ดํ ์ฐ๊ตฌ
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ผ๋ฌธ(์์ฌ)--์์ธ๋ํ๊ต ๋ํ์ :ํ๋๊ณผ์ ์ ์ ๊ณตํ์ ๊ณต,2003.Maste
ํ๊ตญ ์ฒญ์๋ ์ ์ํ ๋ฐ ์์์ ์ญ์ทจ์คํ๊ฐ ๊ณจ๋ฐ๋์ ๋ฏธ์น๋ ์ํฅ
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ผ๋ฌธ(์์ฌ)--์์ธ๋ํ๊ต ๋ณด๊ฑด๋ํ์ :๋ณด๊ฑดํ๊ณผ ๋ณด๊ฑด์์์ ๊ณต,2006.Maste
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