Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3′-Kinase Pathway

Kim, Won; Moon, Sang-Ok; Lee, Sik; Sung, Mi Jeong; Kim, Sung Hoon; Park, Sung Kwang

doi:10.1161/01.atv.0000081740.65173.d1

Cited by 31 publications

(18 citation statements)

References 35 publications

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“…We found that the expression of endothelial adhesion molecules and the subsequent accumulation of leukocytes in the vascular wall were attenuated in induced EC-Akt Tg mice. These results are consistent with a previous study showing that activation of Akt suppresses adhesion molecule expression in vitro (46). The increased production of NO by the Akt induction probably plays an important role in the suppression of inflammatory changes, since NO negatively regulates the expression of adhesion molecules (27,47).…”

Section: Discussionsupporting

confidence: 93%

Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

Mukai

Rikitake

Shiojima

et al. 2006

Journal of Clinical Investigation

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To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with N ω -nitro-l-arginine methyl ester (l-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with l-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.

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Section: Discussionsupporting

confidence: 93%

Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

Mukai

Rikitake

Shiojima

et al. 2006

Journal of Clinical Investigation

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“…In previous studies, treatment with VEGF has been shown to induce adhesion molecules (E-Selectin, VCAM-1 and ICAM-1) in HUVECs(63-65) via an NFKBmediated process. E-Selectin has been shovm to be upregulated by VEGF treatment (66) or in response to inflammation (67,68), and plays an important role in tube formation as well as angiogenesis. E-Selectin also plays a major role in the adhesion of epithelial cancer cells to the endothelium (69).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Early growth response factor 1 (EGRl), SCYA2 (MCP-1), E-Selectin and VCAM-1 are all up-regulated in HUVECs (78,79), and all of these genes are induced by VEGFi2i/rGel treatment. Several members of the small inducible cytokine (SCYA) family of proteins were also over-expressed as a result of VEGFm/rGel treatment.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

Rosenblum¹

2005

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Infonnatlon Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. and TITLE AND SUBTITLEEvaluation of Novel Agents which Target Neovasculature of Breast Tumors AUTHOR(S)Michael Rosenblum, Ph.D. FUNDING NUMBERSDAMD17-02-1-0457 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)The ABSTRACT (Maximum 200 Words)The unique fusion toxin VEGFiji/rGel can specifically kill both log-phase and confluent vascular endothelial cells expressing the KDR receptor for VEGF (PNAS 99:7866,2002). We have discovered 19 unique genes upregulated{>5 fold) in endothelial cells treated with VEGFi2i/rGel(confirmed by Western and RT-PCR).VEGFi2i/rGel(i.v.) treatment had a dramatic cytotoxic effect in both orthotopic and metastatic human breast tumor models. Against the orthotopic model, tumor growth was signi'ficantly delayed by~50%. In addition, tumors completely regressed in 3/6 (50%) of treated mice. In the metastatic breast model, treatment with VEGFiji/rGel reduced both the number and area of lung foci by 58% and 50% respectively and we demonstrated VEGFi2i/rGel(by IHC) on lung tumor vasculature but not normal vasculature. In addition, the number of blood vessels per mm^ in metastatic foci was 198+ 37 versus 388-1-21 for treated and control respectively. Approximately 62% of metastatic colonies from the VEGF/rGel treated group had <10 vessels/colony compared to 23% in the control group. The fll<-l receptor on blood vessel endothelium was intensely expressed on control tumors, but not expressed on treated tumors. Metastatic foci had a 3 fold lower Ki-67 labeling index compared to control tumors. This suggests that VEGFi2i/rGel has impressive antitumor activity in breast cancer. SUBJECT TERMS Reportable Outcomes 16Conclusions 17 References 18Appendices 22 Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors IntroductionBiological studies examining the development of the vascular tree in normal development and in disease states have identified numerous cytokines and their receptors responsible for triggering and maintaining this process (1-7). Tumor neovascularization is central not only to the growth and development of the primary lesion but appears to be a critical factor in the development and maintenance of metastases (8)(9)(10)(11)(12). Clinical studies in bladder cancer (9) have demonstrated a correlation between micro-vessel density and metastases. In addition, studies of breast cancer metastases by have demonstrated that microvessel coimt in primary tumors appears to be related to the presenc...

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“…Furthermore, it was demonstrated that AM inhibited the proinflammatory effects of VEGF such as the induction of the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin. 22 Therefore, AM might cooperate with VEGF to stimulate proliferation and migration of VECs without inducing inflammation in the tissues. Our results support our hypothesis that an artery stenting model is required to analyze the mechanisms of coronary restenosis and explore strategies for the treatment of coronary restenosis.…”

Section: Am Stimulated Reendothelialization and Inhibited Neointimal mentioning

confidence: 99%

Adipose-Derived Stem Cells Stimulate Reendothelialization in Stented Rat Abdominal Aorta

Sato

Takahashi

Fujita

et al. 2014

Circ J

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Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3′-Kinase Pathway

Cited by 31 publications

References 35 publications

Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

Adipose-Derived Stem Cells Stimulate Reendothelialization in Stented Rat Abdominal Aorta

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