36 results on '"Yano, Kiichiro"'
Search Results
2. Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation
- Author
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Zhang, Guoqi, Yang, Li, Kim, Gab Seok, Ryan, Kieran, Lu, Shulin, O'Donnell, Rebekah K., Spokes, Katherine, Shapiro, Nathan, Aird, William C., Kluk, Michael J., Yano, Kiichiro, and Sanchez, Teresa
- Published
- 2013
- Full Text
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3. Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo
- Author
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Jin, Enjing, Liu, Ju, Suehiro, Jun-ichi, Yuan, Lei, Okada, Yoshiaki, Nikolova-Krstevski, Vesna, Yano, Kiichiro, Janes, Lauren, Beeler, David, Spokes, Katherine C., Li, Dan, Regan, Erzsébet, Shih, Shou-Ching, Oettgen, Peter, Minami, Takashi, and Aird, William C.
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- 2009
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4. The down syndrome critical region gene 1 short variant promoters direct vascular bed--specific gene expression during inflammation in mice
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Minami, Takashi, Yano, Kiichiro, Miura, Mai, Kobayashi, Mika, Suehiro, Jun-ichi, Reid, Patrick C., Hamakubo, Takao, Ryeom, Sandra, Aird, William C., and Kodama, Tatsuhiko
- Subjects
Calcineurin -- Health aspects ,Calcineurin -- Genetic aspects ,Calcineurin -- Research ,Down syndrome -- Risk factors ,Down syndrome -- Research ,Gene expression -- Research ,Mice -- Usage ,Mice -- Models - Abstract
Down syndrome critical region gene 1 (DSCR-1) short variant (DSCR-1s) is an inhibitor of calcineurin/NFAT signaling encoded by exons 4-7 of DSCR1. We previously reported that VEGF induces DSCR-1s expression in endothelial cells, which in turn negatively feeds back to attenuate endothelial cell activation. Here, in order to characterize the role of the promoter that drives DSCR-1s expression in mediating inducible expression in vivo and to determine the functional relevance of DSCR-1s in inflammation, we targeted a DNA construct containing 1.7 kb of the human DSCR1s promoter coupled to the lacZ reporter to the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus of mice. We determined that lacZ was uniformly expressed in the endothelium of transgenic embryos but was markedly downregulated postnatally. Systemic administration of VEGF or LPS in adult mice resulted in cyclosporine A--sensitive reactivation of the DSCR1s promoter and endogenous gene expression in a subset of organs, including the heart and brain. The DSCR1s promoter was similarly induced in the endothelium of tumor xenografts. In a mouse model of endotoxemia, DSCR-1s--deficient mice demonstrated increased sepsis mortality, whereas adenovirus-mediated DSCR-1s overexpression protected against LPS-induced lethality. Collectively, these data suggest that the DSCR1s promoter directs vascular bed--specific expression in activated endothelium and that DSCR-1s serves to dampen the host response to infection., Introduction Endothelial cell phenotypes vary in structure and function, in space and time, and in health and disease (reviewed in refs. (1), (2)). Endothelial cells are adapted to meet the [...]
- Published
- 2009
5. Vascular bed-specific endothelium-dependent vasomomotor relaxation in the hagfish, Myxine glutinosa
- Author
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Feng, Jun, Yano, Kiichiro, Monahan-Earley, Rita, Morgan, Ellen S., Dvorak, Ann M., Sellke, Frank W., and Aird, William C.
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Hagfishes -- Physiological aspects ,Vascular endothelium -- Physiological aspects ,Cardiovascular system -- Research ,Biological sciences - Abstract
The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates that lived some time more than 500 million years ago. Features that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. We recently reported that hagfish endothelium displays phenotypic heterogeneity in ultrastructure, lectin binding, and mechanisms of leukocyte adhesion. Thus, phenotypic cell heterogeneity evolved as an early feature of the endothelium. In the present study, we wanted to extend these observations by determining whether hagfish endothelium plays a role in mediating vasomotor tone. Response of mesenteric and skeletal muscle arteries to a variety of mediators was assayed by videomicroscopy. Phenylephrine and acetylcholine induced vasoconstriction of mesenteric and skeletal muscle arteries. Bradykinin (BK) and ADP promoted vasorelaxation in precontracted mesenteric arteries but not those from skeletal muscle. BK- and ADP-mediated vasorelaxation of the mesenteric artery was abrogated by mechanical denudation of the endothelium but was unaffected by [N.sup.G]-nitro-L-arginine methyl ester. Indomethacin significantly inhibited the vasodilatory response to ADP but not BK. The nitric oxide donor sodium nitroprusside resulted in endothelium-independent relaxation of both mesenteric and skeletal muscle arteries. Together, these data suggest that site-specifc endothelium-dependent vasorelaxation is an evolutionarily conserved property of this cell lineage. endothelium; hagfish; vasomotor tone
- Published
- 2007
6. Skin Biopsies Demonstrate Site-Specific Endothelial Activation in Mouse Models of Sepsis
- Author
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Shapiro, Nathan I., Yano, Kiichiro, Sorasaki, Midori, Fischer, Chris, Shih, Shou-Ching, and Aird, William C.
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- 2009
- Full Text
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7. Vascular endothelial growth factor promotes sensitivity to ultraviolet B–induced cutaneous photodamage
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Hirakawa, Satoshi, Fujii, Seishiro, Kajiya, Kentaro, Yano, Kiichiro, and Detmar, Michael
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- 2005
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8. Saccharomyces cerevisiae YDR1, which encodes a member of the ATP-binding cassette (ABC) superfamily, is required for multidrug resistance
- Author
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Hirata, Dai, Yano, Kiichiro, Miyahara, Kohji, and Miyakawa, Tokichi
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- 1994
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9. Stress-induced transcriptional activation mediated by YAP1 and YAP2 genes that encode the Jun family of transcriptional activators in Saccharomyces cerevisiae
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Hirata, Dai, Yano, Kiichiro, and Miyakawa, Tokichi
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- 1994
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10. Ultraviolet B-Induced Skin Angiogenesis Is Associated with a Switch in the Balance of Vascular Endothelial Growth Factor and Thrombospondin-1 Expression
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Yano, Kiichiro, Kajiya, Kentaro, Ishiwata, Miki, Hong, Young-Kwon, Miyakawa, Tokichi, and Detmar, Michael
- Published
- 2004
11. Thrombospondin-1 Plays a Critical Role in the Induction of Hair Follicle Involution and Vascular Regression During the Catagen Phase
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Yano, Kiichiro, Brown, Lawrence F., Lawler, Jack, Miyakawa, Tokichi, and Detmar, Michael
- Published
- 2003
12. Differential Effects of Photoaging vs Intrinsic Aging on the Vascularization of Human Skin
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Chung, Jin Ho, Yano, Kiichiro, Lee, Mi Kyung, Youn, Choon Shik, Seo, Jin Young, Kim, Kyu Han, Cho, Kwang Hyun, Eun, Hee Chul, and Detmar, Michael
- Published
- 2002
13. Targeted Overexpression of the Angiogenesis Inhibitor Thrombospondin-1 in the Epidermis of Transgenic Mice Prevents Ultraviolet-B-Induced Angiogenesis and Cutaneous Photo-Damage
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Yano, Kiichiro, Oura, Hajimu, and Detmar, Michael
- Published
- 2002
14. Control of hair growth and follicle size by VEGF-mediated angiogenesis
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Yano, Kiichiro, Brown, Lawrence F., and Detmar, Michael
- Published
- 2001
15. A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo
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Okada, Yoshiaki, Jin, Enjing, Nikolova-Krstevski, Vesna, Yano, Kiichiro, Liu, Ju, Beeler, David, Spokes, Katherine, Kitayama, Mie, Funahashi, Nobuaki, Doi, Takefumi, Janes, Lauren, Minami, Takashi, Oettgen, Peter, and Aird, William C.
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- 2008
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16. Adiponectin Diminishes Organ-Specific Microvascular Endothelial Cell Activation Associated With Sepsis.
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Van Meurs, Matijs, Castro, Pedro, Shapiro, Nathan I., Lu, Shulin, Yano, Midori, Maeda, Norikazu, Funahashi, Tohru, Shimomura, Ichiro, Zijlstra, Jan G., Molema, Grietje, Parikh, Samir M., Aird, William C., and Yano, Kiichiro
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- 2012
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17. Abnormal Coagulation Tests Obtained in the Emergency Department are Associated with Mortality in Patients with Suspected Infection
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Fischer, Christopher M., Yano, Kiichiro, Aird, William C., and Shapiro, Nathan I.
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EMERGENCY medical services , *BLOOD coagulation tests , *MORTALITY , *HEMATOLOGY , *THROMBOPLASTIN , *COHORT analysis , *INFECTION - Abstract
Abstract: Background: Early recognition of acute organ dysfunction in emergency department (ED) patients with suspected infection may help select patients at increased risk of mortality. The hematologic system is often overlooked in the evaluation and management of patients with infection because it is poorly circumscribed and serves a multitude of functions. Study Objectives: We examine the hypothesis that abnormalities in commonly and easily obtained markers of coagulation function (international normalized ratio [INR], partial thromboplastin time [PTT], and platelet count [PLT]) are associated with mortality in ED patients admitted to the hospital with suspected infection. Methods: Design: Secondary analysis of a prospective observational cohort study. Setting: Urban tertiary care university hospital with 50,000 annual ED visits. Patients: Included patients: adults (age 18 ≥ years) evaluated in the ED for a suspected infection, had an INR, PTT, and PLT obtained during the ED stay, admitted to the hospital. Excluded patients: on oral anticoagulant therapy, received heparin, or pre-existing severe liver disease. Results: There were 1688 patients included. The in-hospital mortality rate was 5.9%. After adjusting for elderly status, comorbid illness burden, and severity of illness, elevated INR was associated with a 2.9 (95% confidence interval [CI] 1.6–5.2) increased odds of death, and a low platelet count (< 150,000/uL) was associated with 2.0 (95% CI 1.2–3.3) increased odds of death. The C-statistic for the model was 0.80. Conclusion: We found an independent association between abnormalities in the coagulation system and mortality in ED patients with suspected infection. These findings underscore the close interaction between inflammation and coagulation and provide evidence that these simple laboratory tests should be routinely considered during the early evaluation of the infected patient. [Copyright &y& Elsevier]
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- 2012
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18. Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene.
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Yuan, Lei, Nikolova-Krstevski, Vesna, Zhan, Yumei, Kondo, Maiko, Bhasin, Manoj, Varghese, Laya, Yano, Kiichiro, Carman, Chris V., Aird, William C., and Oettgen, Peter
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TRANSCRIPTION factors ,INTERLEUKIN-8 ,CADHERINS ,VON Willebrand factor ,TUMOR necrosis factors ,RNA - Abstract
The article presents a study which characterizes the role of ETS-Related Gene (ERG) in the regulation of endothelial cells (EC) function through RNA interference. It mentions that ERG plays a role as a transcriptional repressor of interleukin (IL)-8 in ECs. It also states that it serves as a regulator of EC-restricted genes such as VE-cadherin, von Willebrand factor, and endoglin. Further, ERG portrays a more EC-restricted pattern of expression in cultured cells and in vivo in different organs.
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- 2009
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19. A PROSPECTIVE, OBSERVATIONAL STUDY OF SOLUBLE FLT-1 AND VASCULAR ENDOTHELIAL GROWTH FACTOR IN SEPSIS.
- Author
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Shapiro, Nathan I., Yano, Kiichiro, Okada, Hitomi, Fischer, Christopher, Howell, Michael, Spokes, Katherine C., Ngo, Long, Angus, Derek C., and Aird, William C.
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- 2008
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20. Vascular bed-specific endothelium-dependent vasomomotor relaxation in the hagfish, Myxine glutinosa.
- Author
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Jun Feng, Yano, Kiichiro, Monahan-Eariey, Rita, Morgan, Ellen S., Dvorak, Ann M., Sellke, Frank W., and Aird, William C.
- Subjects
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ATLANTIC hagfish , *ENDOTHELIUM , *VASOMOTOR system , *MYXINE , *RELAXATION for health - Abstract
The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates that lived some time more than 500 million years ago. Features that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. We recently reported that hagfish endothelium displays phenotypic heterogeneity in ultrastructure, lectin binding, and mechanisms of leukocyte adhesion. Thus, phenotypic cell heterogeneity evolved as an early feature of the endothelium. In the present study, we wanted to extend these observations by determining whether hagfish endothelium plays a role in mediating vasomotor tone. Response of mesenteric and skeletal muscle arteries to a variety of mediators was assayed by videomicroscopy. Phenylephrine and acetylcholine induced vasoconstriction of mesenteric and skeletal muscle arteries. Bradykinin (BK) and ADP promoted vasorelaxation in precontracted mesenteric arteries but not those from skeletal muscle. BK- and ADP-mediated vasorelaxation of the mesenteric artery was abrogated by mechanical denudation of the endothelium but was unaffected by Nω-nitro-L-arginine methyl ester. Indomethacin significantly inhibited the vasodilatory response to ADP but not BK. The nitric oxide donor sodium nitroprusside resulted in endothelium-independent relaxation of both mesenteric and skeletal muscle arteries. Together, these data suggest that site-specific endothelium-dependent vasorelaxation is an evolutionarily conserved property of this cell lineage. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
21. A Three-Kilobase Fragment of the Human Robo4 Promoter Directs Cell Type-Specific Expression in Endothelium.
- Author
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Okada, Yoshiaki, Yano, Kiichiro, Jin, Enjing, Funahashi, Nobuaki, Kitayama, Mie, Doi, Takefumi, Spokes, Katherine, Beeler, David L., Shih, Shu-Ching, Okada, Hitomi, Danilov, Tatyana A., Maynard, Elizabeth, Minami, Takashi, Oettgen, Peter, and Aird, William C.
- Published
- 2007
- Full Text
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22. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality.
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Yano, Kiichiro, Liaw, Patricia C., Mullington, Janet M., Shu-Ching Shih, Okada, Hitomi, Bodyak, Natalya, Kang, Peter M., Toltl, Lisa, Belikoff, Bryan, Buras, Jon, Simms, Benjamin T., Mizgerd, Joseph P., Carmeliet, Peter, Karumanchi, S. Ananth, and Aird, William C.
- Subjects
VASCULAR endothelial growth factors ,IMMUNOGLOBULINS ,SEPSIS ,MORTALITY ,BLOOD coagulation ,THERAPEUTICS - Abstract
Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Fit-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PIGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PIGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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23. Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia.
- Author
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Abid, Md. Ruhul, Yano, Kiichiro, Guo, Shaodong, Patel, Virendra I., Shrikhande, Gautam, Spokes, Katherine C., Ferran, Christiane, and Aird, William C.
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TRANSCRIPTION factors , *VASCULAR smooth muscle , *MUSCLE cells , *HYPERPLASIA , *CELL proliferation , *CELL migration , *CELLULAR pathology , *BIOCHEMISTRY - Abstract
Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-α, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK½ and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-α, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27 kip1, and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27kip1. In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27kip1 in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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24. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice.
- Author
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Streit, Michael, Velasco, Paula, Riccardi, Lucia, Spencer, Lisa, Brown, Lawrence F., Janes, Lauren, Lange-Asschenfeldt, Bernhard, Yano, Kiichiro, Hawighorst, Thomas, Iruela-Arispe, Luisa, and Detmar, Michael
- Subjects
THROMBOSPONDINS ,NEOVASCULARIZATION inhibitors ,NEOVASCULARIZATION ,GLYCOPROTEINS ,TISSUES ,MEDICAL research - Abstract
The function of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in tissue repair has remained controversial. We established transgenic mice with targeted overexpression of TSP-1 in the skin, using a keratin 14 expression cassette. TSP-1 transgenic mice were healthy and fertile, and did not show any major abnormalities of normal skin vascularity, cutaneous vascular architecture, or microvascular permeability. However, healing of full-thickness skin wounds was greatly delayed in TSP-1 transgenic mice and was associated with reduced granulation tissue formation and highly diminished wound angiogenesis. Moreover, TSP-1 potently inhibited libroblast migration/n vivo and in vitro. These findings demonstrate that TSP-1 preferentially interfered with wound healing-associated angiogenesis, rather than with the angiogenesis associated with normal development and skin homeostasis, and suggest that therapeutic application of angiogenesis inhibitors might potentially be associated with impaired wound vascularization and tissue repair. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
25. Vascular endocan is preferentially expressed in tumor endothelium
- Author
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Abid, Md. Ruhul, Yi, Xianjin, Yano, Kiichiro, Shih, Shu-Ching, and Aird, William C.
- Subjects
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PROTEOGLYCANS , *ENDOTHELIUM , *BLOOD vessels , *VASCULAR endothelial growth factors - Abstract
Abstract: Endothelial cell phenotypes are differentially regulated between different sites of the vascular tree. We tested the hypothesis that endocan, a novel soluble dermatan sulfate proteoglycan, is differentially expressed in the intact endothelium and that site-specific expression is mediated by signals in the local microenvironment. Using a combination of Northern blot analyses, Taqman RT-PCR, and in situ hybridizations, endocan was shown to be preferentially expressed in the endothelial lining of tumor xenografts, including human non-small cell lung cancer, rat glioma, and human renal cell carcinoma. In contrast, endocan mRNA was expressed at low levels in embryos between E4.5 and E18.5. Under in vitro conditions, endocan expression in human umbilical vein endothelial cells (HUVEC) was upregulated by tumor cell-conditioned medium, an effect that was inhibited by the addition of neutralizing antibody to vascular endothelial growth factor (VEGF). Moreover, treatment of HUVEC with VEGF resulted in a dose- and time-dependent increase in endocan mRNA. The results suggest that endocan is preferentially expressed in tumor endothelium in vivo and that its expression is regulated by tumor-derived factors. [Copyright &y& Elsevier]
- Published
- 2006
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26. Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation.
- Author
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Guoqi Zhang, Li Yang, Gab Seok Kim, Ryan, Kieran, Shulin Lu, O'Donnell, Rebekah K., Spokes, Katherine, Shapiro, Nathan, Aird, William C., Kluk, Michael J., Yano, Kiichiro, and Sanchez, Teresa
- Subjects
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ENDOTHELIUM , *SPHINGOSINE-1-phosphate , *INFLAMMATION , *SPHINGOLIPIDS , *BLOOD plasma - Abstract
The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1 PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotox-emia. Experiments with bone marrow chimeras (S1pr2+/+ →S1pr2+/+, S1pr2+/+ → S1pr2-/-, and S1pr2-/- → S1pr2+/+) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor α-induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1 PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
27. Critical Role for GATA3 in Mediating Tie2 Expression and Function in Large Vessel Endothelial Cells.
- Author
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Haihua Song, Jun-ichi Suehiro, Kanki, Yasuharu, Kawai, Yoshiko, lnoue, Kenji, Daida, Hiroyuki, Yano, Kiichiro, Ohhashi, Toshio, Oettgen, Peter, Aird, William C., Kodama, Tatsuhiko, and Minami, Takashi
- Subjects
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PHENOTYPES , *TRANSCRIPTION factors , *CELLULAR signal transduction , *DNA microarrays , *GROWTH factors , *TUMOR necrosis factors , *CELL adhesion - Abstract
Endothelial phenotypes are highly regulated in space and time by both transcriptional and post-transcriptional mechanisms. There is increasing evidence that the GATA family of transcription factors function as signal transducers, coupling changes in the extracellular environment to changes in downstream target gene expression. Here we show that human primary endothelial cells derived from large blood vessels express GATA2, -3, and -6. Of these factors, GATA3 was expressed at the highest levels. In DNA microarrays of human umbilical vein endothelial cells (HUVEC), small interfering RNA-mediated knockdown of GATA3 resulted in reduced expression of genes associated with angiogenesis, including Tie2. At a functional level, GATA3 knockdown inhibited angiopoietin (Ang)1-mediated but not vascular endothelial cell growth factor (VEGF)-mediated AKT signaling, cell migration, survival, and tube formation. In electrophoretic gel mobility shift assays and chromatin immunoprecipitation, GATA3 was shown to bind to regulatory regions within the 5'-untranslated region of the Tie2 gene. In co-immunoprecipitation and co-transfection assays, GATA3 and the Ets transcription factor, ELF 1, physically interacted and synergized to transactivate the Tie2 promoter. GATA3 knockdown blocked the ability of Ang1 to attenuate vascular endothelial cell growth factor stimulation of vascular cell adhesion molecule-1 expression and monocytic cell adhesion. Moreover, exposure of human umbilical vein endothelial cells to tumor necrosis factor-α resulted in marked down-regulation of GATA3 expression and reduction in Tie2 expression. Together, these findings suggest that GATA3 is indispensable for Ang-1-Tie2-mediated signaling in large vessel endothelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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28. Hair Follicle Regeneration Using Grafted Rodent and Human Cells.
- Author
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Ehama, Ritsuko, Ishimatsu-Tsuji, Yumiko, Iriyama, Shunsuke, Ideta, Ritsuro, Soma, Tsutomu, Yano, Kiichiro, Kawasaki, Chikako, Suzuki, Satoshi, Shirakata, Yuji, Hashimoto, Koji, and Kishimoto, Jiro
- Subjects
- *
HAIR follicles , *REGENERATION (Biology) , *EPITHELIAL cells , *KERATINOCYTES , *EPIDERMIS - Abstract
Hair follicle regeneration involves epithelial–mesenchymal interactions (EMIs) of follicular epithelial and dermal papilla (DP) cells. Co-grafting of those cellular components from mice allows complete hair reconstitution. However, regeneration of human hair in a similar manner has not been reported. Here, we investigated the possibility of cell-based hair generation from human cells. We found that DP-enriched cells (DPE) are more critical than epidermal cells in murine hair reconstitution on a cell number basis, and that murine DPE are also competent for hair regeneration with rat epidermal cells. Co-grafting of human keratinocytes derived from neonatal foreskins with murine DPE produced hair follicle-like structures consisting of multiple epidermal cell layers with a well-keratinized innermost region. Those structures expressed hair follicle-specific markers including hair keratin, and markers expressed during developmental stages. However, the lack of regular hair structures indicates abnormal folliculogenesis. Similar hair follicle-like structures were also generated with cultured human keratinocytes after the first passage, or with keratinocytes derived from adult foreskins, demonstrating that epidermal cells even at a mature stage can differentiate in response to inductive signals from DP cells. This study emphasizes the importance of EMI in follicular generation and the differentiation potential of epidermal keratinocytes.Journal of Investigative Dermatology (2007) 127, 2106–2115; doi:10.1038/sj.jid.5700823; published online 12 April 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
29. The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation.
- Author
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Shirakura K, Ishiba R, Kashio T, Funatsu R, Tanaka T, Fukada SI, Ishimoto K, Hino N, Kondoh M, Ago Y, Fujio Y, Yano K, Doi T, Aird WC, and Okada Y
- Subjects
- Amino Acid Sequence, Animals, Antigens, CD metabolism, Cadherins metabolism, Disease Models, Animal, Endothelium, Vascular metabolism, Endotoxemia chemically induced, Inflammation etiology, Inflammation metabolism, Male, Mice, Mice, Knockout, Neovascularization, Pathologic etiology, Neovascularization, Pathologic metabolism, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics, Cell Membrane Permeability, Endothelium, Vascular pathology, Endotoxemia complications, Inflammation pathology, Neovascularization, Pathologic pathology, Receptors, Cell Surface physiology, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins metabolism
- Abstract
Roundabout guidance receptor 4 (Robo4) is an endothelial cell-specific receptor that stabilizes the vasculature in pathological angiogenesis. Although Robo4 has been shown to suppress vascular hyperpermeability induced by vascular endothelial growth factor (VEGF) in angiogenesis, the role of Robo4 in inflammation is poorly understood. In this study, we investigated the role of Robo4 in vascular hyperpermeability during inflammation. Endotoxemia models using Robo4
-/- mice showed increased mortality and vascular leakage. In endothelial cells, Robo4 suppressed tumor necrosis factor α (TNFα)-induced hyperpermeability by stabilizing VE-cadherin at cell junctions, and deletion assays revealed that the C-terminus of Robo4 was involved in this suppression. Through binding and localization assays, we demonstrated that in endothelial cells, Robo4 binds to TNF receptor-associated factor 7 (TRAF7) through interaction with the C-terminus of Robo4. Gain- and loss-of-function studies of TRAF7 with or without Robo4 expression showed that TRAF7 is required for Robo4-mediated suppression of hyperpermeability. Taken together, our results demonstrate that the Robo4-TRAF7 complex is a novel negative regulator of inflammatory hyperpermeability. We propose this complex as a potential future target for protection against inflammatory diseases., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)- Published
- 2019
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30. A Vascular Permeability Assay Using an In Vitro Human Microvessel Model Mimicking the Inflammatory Condition.
- Author
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Pauty J, Usuba R, Takahashi H, Suehiro J, Fujisawa K, Yano K, Nishizawa T, and Matsunaga YT
- Abstract
The vascular barrier is an important function of the endothelium and its dysfunction is involved in several diseases. The barrier function of the endothelial cell monolayer is governed by cell-cell, cell-extracellular matrix (cell-ECM) contacts, and inflammatory factors such as thrombin, histamine or vascular endothelial growth factor. Several in vivo and in vitro assays that measure the vascular permeability induced by these factors have been developed. However, they suffer limitations such as being challenging for assessing details of biological processes at a cellular level or lacking the architecture of a vessel, that raise the need for new methods. In vitro 3D model-based assays have thus been developed but assays for investigating compounds that protects the barrier function are lacking. Here we describe the development of an in vitro three-dimensional (3D) vascular endothelium model in which we can manipulate the endothelial barrier function and permeability to molecules, which have a molecular weight similar to human serum albumin, allowing to assess the protective effect of compounds. A microvessel was prepared by culturing human umbilical vein endothelial cells (HUVECs) within a collagen gel on a polydimethylsiloxane (PDMS) chip. Using fluorescein isothiocyanate (FITC)-conjugated dextran (70 kDa, FITC-dextran) and confocal fluorescence microscopy, we showed that the microvessel presented an effective barrier function. We were then able to induce the loss of this barrier function by treatment with the inflammatory factor thrombin. The loss of barrier function was quantified by the extravasation of FITC-dextran into collagen matrix. Furthermore, we were able to analyze the protective effect on the endothelial barrier function of the cyclic adenosine monophosphate (cAMP) analog, 8-pCPT-2'-O-Me-cAMP (also called 007). In an attempt to understand the effects of thrombin and 007 in our model, we analyzed the adherens junctions and cytoskeleton through immunostaining of the vascular endothelial cadherin and actin, respectively. Our assay method could be used to screen for compounds modulating the barrier function of endothelial cells, as well as investigating mechanistic aspects of barrier dysfunction., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
- Published
- 2017
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31. Leptin exacerbates sepsis-mediated morbidity and mortality.
- Author
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Shapiro NI, Khankin EV, Van Meurs M, Shih SC, Lu S, Yano M, Castro PR, Maratos-Flier E, Parikh SM, Karumanchi SA, and Yano K
- Subjects
- Animals, Cell Line, Tumor, Cells, Cultured, Endothelium, Vascular immunology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Endotoxemia metabolism, Humans, Leptin blood, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Monocytes immunology, Monocytes metabolism, Monocytes pathology, Morbidity, Prospective Studies, Protein Isoforms administration & dosage, Protein Isoforms blood, Receptors, Leptin blood, Receptors, Leptin deficiency, Receptors, Leptin physiology, Recombinant Proteins administration & dosage, Recombinant Proteins blood, Severity of Illness Index, Endotoxemia immunology, Endotoxemia mortality, Leptin adverse effects
- Abstract
The adipose-derived hormone leptin is well known for its contribution to energy metabolism and satiety signaling in the hypothalamus. Previous studies suggested that obesity is an independent risk factor for sepsis morbidity and mortality, and it is associated with elevated baseline levels of circulating leptin in normal, nonseptic patients. In mouse endotoxemia and cecal ligation puncture models of sepsis, we observed elevated levels of leptin and soluble leptin receptor (sLR). Exogenously administered leptin increased mortality in endotoxemia and cecal ligation puncture models and was associated with increased expression of adhesion and coagulation molecules, macrophage infiltration into the liver and kidney, and endothelial barrier dysfunction. Conversely, longform leptin receptor-deficient mice were protected from sepsis morbidity and mortality and had less endothelial dysfunction. Furthermore, an in vitro study revealed that leptin-induced endothelial dysfunction is likely mediated, at least in part, by monocytes. Moreover, administration of an sLR conferred a survival benefit. Human septic patients have increased circulating sLR concentrations, which were correlated with disease severity indices. Together, these data support a pathogenic role for leptin signaling during sepsis.
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- 2010
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32. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis.
- Author
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Shapiro NI, Schuetz P, Yano K, Sorasaki M, Parikh SM, Jones AE, Trzeciak S, Ngo L, and Aird WC
- Subjects
- Adult, Aged, Biomarkers metabolism, Cohort Studies, Female, Hospital Mortality trends, Humans, Male, Middle Aged, Multiple Organ Failure complications, Plasminogen Activator Inhibitor 1 metabolism, Prospective Studies, Sepsis complications, Vascular Cell Adhesion Molecule-1 metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism, Endothelial Cells metabolism, Multiple Organ Failure metabolism, Multiple Organ Failure pathology, Sepsis metabolism, Sepsis pathology, Severity of Illness Index, Signal Transduction physiology
- Abstract
Introduction: Previous reports suggest that endothelial activation is an important process in sepsis pathogenesis. We investigated the association between biomarkers of endothelial cell activation and sepsis severity, organ dysfunction sequential organ failure assessment (SOFA) score, and death., Methods: This is a prospective, observational study including adult patients (age 18 years or older) presenting with clinical suspicion of infection to the emergency department (ED) of an urban, academic medical center between February 2005 and November 2008. Blood was sampled during the ED visit and biomarkers of endothelial cell activation, namely soluble fms-like tyrosine kinase-1 (sFlt-1), plasminogen activator inhibitors -1 (PAI-1), sE-selectin, soluble intercellular adhesion molecule (sICAM-1), and soluble vascular cell adhesion molecule (sVCAM-1), were assayed. The association between biomarkers and the outcomes of sepsis severity, organ dysfunction, and in-hospital mortality were analyzed., Results: A total of 221 patients were included: sepsis without organ dysfunction was present in 32%, severe sepsis without shock in 30%, septic shock in 32%, and 6% were non-infected control ED patients. There was a relationship between all target biomarkers (sFlt-1, PAI-1, sE-selectin, sICAM-1, and sVCAM-1) and sepsis severity, P < 0.05. We found a significant inter-correlation between all biomarkers, including the strongest correlations between sFlt-1 and sE-selectin (r = 0.55, P < 0.001), and between sFlt-1 and PAI-1 (0.56, P < 0.001). Among the endothelial cell activation biomarkers, sFlt-1 had the strongest association with SOFA score (r = 0.66, P < 0.001), the highest area under the receiver operator characteristic curve for severe sepsis of 0.82, and for mortality of 0.91., Conclusions: Markers of endothelial cell activation are associated with sepsis severity, organ dysfunction and mortality. An improved understanding of endothelial response and associated biomarkers may lead to strategies to more accurately predict outcome and develop novel endothelium-directed therapies in sepsis.
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- 2010
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33. Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.
- Author
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Song H, Suehiro J, Kanki Y, Kawai Y, Inoue K, Daida H, Yano K, Ohhashi T, Oettgen P, Aird WC, Kodama T, and Minami T
- Subjects
- Angiopoietin-1 metabolism, Endothelial Cells cytology, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, GATA3 Transcription Factor metabolism, Humans, Immunoprecipitation, Oligonucleotide Array Sequence Analysis, Phenotype, Promoter Regions, Genetic, RNA, Small Interfering metabolism, Receptor, TIE-2 chemistry, Tumor Necrosis Factor-alpha metabolism, Umbilical Veins cytology, Vascular Endothelial Growth Factor A metabolism, GATA3 Transcription Factor physiology, Gene Expression Regulation, Receptor, TIE-2 biosynthesis
- Abstract
Endothelial phenotypes are highly regulated in space and time by both transcriptional and post-transcriptional mechanisms. There is increasing evidence that the GATA family of transcription factors function as signal transducers, coupling changes in the extracellular environment to changes in downstream target gene expression. Here we show that human primary endothelial cells derived from large blood vessels express GATA2, -3, and -6. Of these factors, GATA3 was expressed at the highest levels. In DNA microarrays of human umbilical vein endothelial cells (HUVEC), small interfering RNA-mediated knockdown of GATA3 resulted in reduced expression of genes associated with angiogenesis, including Tie2. At a functional level, GATA3 knockdown inhibited angiopoietin (Ang)-1-mediated but not vascular endothelial cell growth factor (VEGF)-mediated AKT signaling, cell migration, survival, and tube formation. In electrophoretic gel mobility shift assays and chromatin immunoprecipitation, GATA3 was shown to bind to regulatory regions within the 5'-untranslated region of the Tie2 gene. In co-immunoprecipitation and co-transfection assays, GATA3 and the Ets transcription factor, ELF1, physically interacted and synergized to transactivate the Tie2 promoter. GATA3 knockdown blocked the ability of Ang-1 to attenuate vascular endothelial cell growth factor stimulation of vascular cell adhesion molecule-1 expression and monocytic cell adhesion. Moreover, exposure of human umbilical vein endothelial cells to tumor necrosis factor-alpha resulted in marked down-regulation of GATA3 expression and reduction in Tie2 expression. Together, these findings suggest that GATA3 is indispensable for Ang-1-Tie2-mediated signaling in large vessel endothelial cells.
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- 2009
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34. Elevated levels of placental growth factor represent an adaptive host response in sepsis.
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Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, and Aird WC
- Subjects
- Analysis of Variance, Animals, Immunohistochemistry, In Situ Hybridization, Mice, Placenta Growth Factor, Pregnancy Proteins genetics, Pregnancy Proteins metabolism, Sepsis metabolism, Gene Expression Regulation immunology, Pregnancy Proteins immunology, Sepsis immunology, Signal Transduction immunology, Vascular Endothelial Growth Factor A metabolism
- Abstract
Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447-1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G-injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.
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- 2008
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35. Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium.
- Author
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Yano K, Gale D, Massberg S, Cheruvu PK, Monahan-Earley R, Morgan ES, Haig D, von Andrian UH, Dvorak AM, and Aird WC
- Subjects
- Animals, Aorta ultrastructure, Biological Evolution, Capillaries cytology, Cell Adhesion, Dermis blood supply, Dermis ultrastructure, Heart anatomy & histology, Lectins, Leukocytes cytology, Liver ultrastructure, Phenotype, Staining and Labeling, Venules cytology, Endothelium ultrastructure, Hagfishes physiology
- Abstract
Mammalian endothelial cells (ECs) display marked phenotypic heterogeneity. Little is known about the evolutionary mechanisms underlying EC heterogeneity. The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates, which lived some time more than 500 million years ago. Features of ECs that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. The goal of this study was to determine whether the hagfish endothelium displays phenotypic heterogeneity. Electron microscopy of the aorta, dermis, heart, and liver revealed ultrastructural heterogeneity of the endothelium. Immunofluorescent studies demonstrated marked differences in lectin binding between vascular beds. Intravital microscopy of the dermis revealed histamine-induced adhesion of leukocytes in capillaries and postcapillary venules, but no such adhesion in arterioles. Together, these data suggest that structural, molecular, and functional heterogeneity of the endothelium evolved as an early feature of this cell lineage.
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- 2007
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36. Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression.
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Inoue K, Kobayashi M, Yano K, Miura M, Izumi A, Mataki C, Doi T, Hamakubo T, Reid PC, Hume DA, Yoshida M, Aird WC, Kodama T, and Minami T
- Subjects
- Animals, Azepines pharmacology, Cell Adhesion drug effects, Cell Adhesion physiology, Chromones pharmacology, E-Selectin genetics, E-Selectin metabolism, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Enzyme Inhibitors pharmacology, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Histone Deacetylases genetics, Histone Deacetylases metabolism, Histone Deacetylases physiology, Humans, Hydroxamic Acids pharmacology, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Leupeptins pharmacology, Mice, Mice, Transgenic, Monocytes drug effects, Morpholines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction drug effects, Signal Transduction physiology, Transcriptional Activation, Tumor Necrosis Factor-alpha pharmacology, Vascular Cell Adhesion Molecule-1 genetics, Endothelium, Vascular metabolism, Histone Deacetylase Inhibitors, Monocytes cytology, Monocytes metabolism, Vascular Cell Adhesion Molecule-1 metabolism
- Abstract
Objective: Tumor necrosis factor (TNF)-alpha initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-alpha-mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-alpha-responsive genes and functions., Methods and Results: Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF-alpha at 4 hours and analyzed by microarray. TNF-alpha-mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-alpha-mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-alpha-mediated VCAM-1 expression., Conclusions: TNF-alpha activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM-1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.
- Published
- 2006
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