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Your search keyword '"Yuldasheva, Nadira"' showing total 167 results
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167 results on '"Yuldasheva, Nadira"'

3. Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction

Author

Espino-Gonzalez, Ever, Tickle, Peter G., Altara, Raffaele, Gallagher, Harrison, Cheng, Chew W., Engman, Viktor, Wood, Nathanael, Justo da Silva, Gustavo Jose, Scalabrin, Mattia, Yu, Xinyue, Zhong, Ziyi, Colman, Michael A., Yuldasheva, Nadira Y., Booz, George W., Adams, Volker, Pereira, Marcelo G., Cataliotti, Alessandro, Roberts, Lee D., Egginton, Stuart, and Bowen, T. Scott

Published
2024
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6. Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Author

Meakin, Paul J., Coull, Bethany M., Tuharska, Zofia, McCaffery, Christopher, Akoumianakis, Ioannis, Antoniades, Charalambos, Brown, Jane, Griffin, Kathryn J., Platt, Fiona, Ozber, Claire H., Yuldasheva, Nadira Y., Makava, Natallia, Skromna, Anna, Prescott, Alan, McNeilly, Alison D., Siddiqui, Moneeza, Palmer, Colin N.A., Khan, Faisel, and Ashford, Michael L.J.

Subjects
Thermo Fisher Scientific Inc., Obesity -- Development and progression, Endothelin, Type 2 diabetes -- Development and progression, Endothelium, Nitric oxide, Enzymes, Vascular diseases -- Development and progression, Advertising executives, Alzheimer's disease -- Development and progression, Amyloid beta-protein, Health care industry, Wellcome Trust
Abstract

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased p-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and [beta]-amyloid (A[beta]) are linked with vascular disease development and increased BACE1 and A[beta] accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased A[beta], and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A[beta]42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A[beta]42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A[beta]42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A[beta]42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A[beta]42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A[beta]42. Lowering A[beta]42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes., Introduction There is increasing evidence that links vascular disease and endothelial dysfunction (as found in obesity, diabetes, and hypercholesterolemia; i.e., metabolic syndrome) with Alzheimer's disease (AD) and cognitive impairment, through [...]

Published
2020
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10. The Eurasian Heartland: A Continental Perspective on Y-Chromosome Diversity

Author

Wells, R. Spencer, Yuldasheva, Nadira, Ruzibakiev, Ruslan, Underhill, Peter A., Evseeva, Irina, Blue-Smith, Jason, Jin, Li, Su, Bing, Pitchappan, Ramasamy, Shanmugalakshmi, Sadagopal, Balakrishnan, Karuppiah, Read, Mark, Pearson, Nathaniel M., Zerjal, Tatiana, Webster, Matthew T., Zholoshvili, Irakli, Jamarjashvili, Elena, Gambarov, Spartak, Nikbin, Behrouz, Dostiev, Ashur, Aknazarov, Ogonazar, Zalloua, Pierre, Tsoy, Igor, Kitaev, Mikhail, Mirrakhimov, Mirsaid, Chariev, Ashir, and Bodmer, Walter F.

Published
2001

12. A fibrin biofilm covers blood clots and protects from microbial invasion

Author

Macrae, Fraser L., Duval, Cedric, Papareddy, Praveen, Baker, Stephen R., Yuldasheva, Nadira, Kearney, Katherine J., McPherson, Helen R., Asquith, Nathan, Konings, Joke, Casini, Alessandro, Degen, Jay L., Connell, Simon D., Philippou, Helen, Wolberg, Alisa S., Herwald, Heiko, and Ariens, Robert A.S.

Subjects
Hemostasis -- Research, Thrombosis -- Care and treatment -- Research, Fibrinogen -- Analysis, Infection -- Health aspects, Blood cells -- Research, Health care industry
Abstract

Hemostasis requires conversion of fibrinogen to fibrin fibers that generate a characteristic network, interact with blood cells, and initiate tissue repair. The fibrin network is porous and highly permeable, but the spatial arrangement of the external clot face is unknown. Here we show that fibrin transitioned to the blood-air interface through Langmuir film formation, producing a protective film confining clots in human and mouse models. We demonstrated that only fibrin is required for formation of the film, and that it occurred in vitro and in vivo. The fibrin film connected to the underlying clot network through tethering fibers. It was digested by plasmin, and formation of the film was prevented with surfactants. Functionally, the film retained blood cells and protected against penetration by bacterial pathogens in a murine model of dermal infection. Our data show a remarkable aspect of blood clotting in which fibrin forms a protective film covering the external surface of the clot, defending the organism against microbial invasion., Introduction Hemostasis is a pivotal mechanism to prevent life-threatening blood loss from sites of injury, and involves close interplay between coagulation and platelets. The resulting blood clot contains activated platelets, [...]

Published
2018
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13. Independent endothelial functions of PIEZO1 and TRPV4 in hepatic portal vein and predominance of PIEZO1 in mechanical and osmotic stress.

Author

Endesh, Naima, Chuntharpursat‐Bon, Eulashini, Revill, Charlotte, Yuldasheva, Nadira Y., Futers, T. Simon, Parsonage, Gregory, Humphreys, Neil, Adamson, Antony, Morley, Lara C., Cubbon, Richard M., Prasad, K. Raj, Foster, Richard, Lichtenstein, Laeticia, and Beech, David J.

Subjects
PORTAL vein, HEPATIC veins, TRPV cation channels, STRAINS & stresses (Mechanics), NITRIC-oxide synthases, ARACHIDONIC acid
Abstract

Background & Aims: PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium‐permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen. Methods: Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non‐disruptive tag in native PIEZO1 or endothelial‐specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively. Results: PIEZO1 activation leads to nitric oxide synthase‐ and endothelium‐dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium‐dependent but independent of nitric oxide synthase. The TRPV4‐mediated contraction is suppressed by inhibitors of phospholipase A2 and cyclooxygenases and mimicked by prostaglandin E2, suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo‐osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses. Conclusions: The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Role of glutamine and interlinked asparagine metabolism in vessel formation

Author

Huang, Hongling, Vandekeere, Saar, Kalucka, Joanna, Bierhansl, Laura, Zecchin, Annalisa, Brüning, Ulrike, Visnagri, Asjad, Yuldasheva, Nadira, Goveia, Jermaine, Cruys, Bert, Brepoels, Katleen, Wyns, Sabine, Rayport, Stephen, Ghesquière, Bart, Vinckier, Stefan, Schoonjans, Luc, Cubbon, Richard, Dewerchin, Mieke, Eelen, Guy, and Carmeliet, Peter

Published
2017
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16. Cardiac q‐space trajectory imaging by motion‐compensated tensor‐valued diffusion encoding in human heart in vivo.

Author

Teh, Irvin, Shelley, David, Boyle, Jordan H., Zhou, Fenglei, Poenar, Ana‐Maria, Sharrack, Noor, Foster, Richard J., Yuldasheva, Nadira Y., Parker, Geoff J. M., Dall'Armellina, Erica, Plein, Sven, Schneider, Jürgen E., and Szczepankiewicz, Filip

Subjects
ENCODING, DIFFUSION tensor imaging
Abstract

Purpose: Tensor‐valued diffusion encoding can probe more specific features of tissue microstructure than what is available by conventional diffusion weighting. In this work, we investigate the technical feasibility of tensor‐valued diffusion encoding at high b‐values with q‐space trajectory imaging (QTI) analysis, in the human heart in vivo. Methods: Ten healthy volunteers were scanned on a 3T scanner. We designed time‐optimal gradient waveforms for tensor‐valued diffusion encoding (linear and planar) with second‐order motion compensation. Data were analyzed with QTI. Normal values and repeatability were investigated for the mean diffusivity (MD), fractional anisotropy (FA), microscopic FA (μFA), isotropic, anisotropic and total mean kurtosis (MKi, MKa, and MKt), and orientation coherence (Cc). A phantom, consisting of two fiber blocks at adjustable angles, was used to evaluate sensitivity of parameters to orientation dispersion and diffusion time. Results: QTI data in the left ventricular myocardium were MD = 1.62 ± 0.07 μm2/ms, FA = 0.31 ± 0.03, μFA = 0.43 ± 0.07, MKa = 0.20 ± 0.07, MKi = 0.13 ± 0.03, MKt = 0.33 ± 0.09, and Cc = 0.56 ± 0.22 (mean ± SD across subjects). Phantom experiments showed that FA depends on orientation dispersion, whereas μFA was insensitive to this effect. Conclusion: We demonstrated the first tensor‐valued diffusion encoding and QTI analysis in the heart in vivo, along with first measurements of myocardial μFA, MKi, MKa, and Cc. The methodology is technically feasible and provides promising novel biomarkers for myocardial tissue characterization. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

Author

Viswambharan, Hema, Yuldasheva, Nadira Y., Sengupta, Anshuman, Imrie, Helen, Gage, Matthew C., Haywood, Natalie, Walker, Andrew M.N., Skromna, Anna, Makova, Natallia, Galloway, Stacey, Shah, Pooja, Sukumar, Piruthivi, Porter, Karen E., Grant, Peter J., Shah, Ajay M., Santos, Celio X.C., Li, Jing, Beech, David J., Wheatcroft, Stephen B., Cubbon, Richard M., and Kearney, Mark T.

Published
2017
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24. Piezo1 integration of vascular architecture with physiological force

Author

Li, Jing, Hou, Bing, Tumova, Sarka, Muraki, Katsuhiko, Bruns, Alexander, Ludlow, Melanie J., Sedo, Alicia, Hyman, Adam J., McKeown, Lynn, Young, Richard S., Yuldasheva, Nadira Y., Majeed, Yasser, Wilson, Lesley A., Rode, Baptiste, Bailey, Marc A., Kim, Hyejeong R., Fu, Zhaojun, Carter, Deborah A. L., Bilton, Jan, Imrie, Helen, Ajuh, Paul, Dear, T. Neil, Cubbon, Richard M., Kearney, Mark T., Prasad, K. Raj, Evans, Paul C., Ainscough, Justin F. X., and Beech, David J.

Subjects
Ion channels -- Research -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Jing Li [1, 6]; Bing Hou [1, 6]; Sarka Tumova [1]; Katsuhiko Muraki [2]; Alexander Bruns [1]; Melanie J. Ludlow [1]; Alicia Sedo [1]; Adam J. Hyman [1]; Lynn [...]

Published
2014
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25. Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.

Author

Imrie, Helen, Viswambharan, Hema, Haywood, Natalie J, Bridge, Katherine I, Yuldasheva, Nadira Y, Galloway, Stacey, Simmons, Katie J, Cubbon, Richard M, Sukumar, Piruthivi, Watt, Nicole T, Lichtenstein, Laeticia, Wyatt, Judy I, Kudo, Hiromi, Goldin, Robert, Rode, Baptiste, Wheatcroft, Stephen B, and Kearney, Mark T

Subjects
TISSUE remodeling, CELL receptors, ADIPOSE tissues, WHITE adipose tissue, HIGH-fat diet
Abstract

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance. [ABSTRACT FROM AUTHOR]

Published
2022
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29. 184 Temporospatial Effects of Endothelium Specific Inhibition of Shc Homology 2 -containing Inositol 5´ Phosphatase 2 on Nitric Oxide Bioavailability and Whole Body Insulin Sensitivity

Author

Gage, Matthew, Viswambharan, Hema, Sukumar, Piruthivi, Cubbon, Richard, Imrie, Helen, Galloway, Stacey, Abbas, Afroze, Yuldasheva, Nadira, Smith, Jessica, Skromna, Anna, Grant, Peter, Gatenby, Victoria, Beech, David, Schurmans, Stephane, Wheatcroft, Stephen, and Kearney, Mark

Published
2014
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33. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Published
2007
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37. The genetic legacy of the Mongols. (Report)

Author

Zerjal, Tatiana, Xue, Yali, Bertorelle, Giorgio, Wells, R. Spencer, Bao, Weidong, Zhu, Suling, Qamar, Raheel, Ayub, Qasim, Mohyuddin, Aisha, Fu, Songbin, Li, Pu, Yuldasheva, Nadira, Ruzibakiev, Ruslan, Xu, Jiujin, Shu, Qunfang, Du, Ruofu, Yang, Huanming, Hurles, Matthew E., Robinson, Elizabeth, Gerelsaikhan, Tudevdagva, Dashnyam, Bumbein, Mehdi, S. Qasim, and Tyler-Smith, Chris

Subjects
Mongols -- Genetic aspects, Natural selection -- Case studies, Natural selection -- Genetic aspects, Genetic research, Biological sciences
Published
2003

39. Novel Role of the IGF-1 Receptor in Endothelial Function and Repair: Studies in Endothelium-Targeted IGF-1 Receptor Transgenic Mice

Author

Imrie, Helen, Viswambharan, Hema, Sukumar, Piruthivi, Abbas, Afroze, Cubbon, Richard M., Yuldasheva, Nadira, Gage, Matthew, Smith, Jessica, Galloway, Stacey, Skromna, Anna, Rashid, Sheik Taqweer, Futers, T. Simon, Xuan, Shouhong, Gatenby, V. Kate, Grant, Peter J., Channon, Keith M., Beech, David J., Wheatcroft, Stephen B., and Kearney, Mark T.

Published
2012
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40. Increasing Circulating IGFBP1 Levels Improves Insulin Sensitivity, Promotes Nitric Oxide Production, Lowers Blood Pressure, and Protects Against Atherosclerosis

Author

Rajwani, Adil, Ezzat, Vivienne, Smith, Jessica, Yuldasheva, Nadira Y., Duncan, Edward R., Gage, Matthew, Cubbon, Richard M., Kahn, Matthew B., Imrie, Helen, Abbas, Afroze, Viswambharan, Hema, Aziz, Amir, Sukumar, Piruthivi, Vidal-Puig, Antonio, Sethi, Jaswinder K., Xuan, Shouhong, Shah, Ajay M., Grant, Peter J., Porter, Karen E., Kearney, Mark T., and Wheatcroft, Stephen B.

Published
2012
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43. Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling.

Author

Warmke, Nele, Platt, Fiona, Bruns, Alexander F, Ozber, Claire H, Haywood, Natalie J, Abudushalamu, Yilizila, Slater, Charles, Palin, Victoria, Sukumar, Piruthivi, Wheatcroft, Stephen B, Yuldasheva, Nadira Y, Kearney, Mark T, Griffin, Kathryn J, and Cubbon, Richard M

Subjects
INSULIN receptors, VASCULAR remodeling, ANGIOPOIETINS
Abstract

Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRβ-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial plexi, and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the perivenous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease. [ABSTRACT FROM AUTHOR]

Published
2021
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44. Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

Author

Viswambharan, Hema, Yuldasheva, Nadira Y., Imrie, Helen, Bridge, Katherine, Haywood, Natalie J., Skromna, Anna, Hemmings, Karen E., Clark, Emily R., Gatenby, V. Kate, Cordell, Paul, Simmons, Katie J., Makava, Natallia, Abudushalamu, Yilizila, Endesh, Naima, Brown, Jane, Walker, Andrew M. N., Futers, Simon T., Porter, Karen E., Cubbon, Richard M., and Naseem, Khalid

Published
2021
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45. Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Author

Walker, Andrew M N, Warmke, Nele, Mercer, Ben, Watt, Nicole T, Mughal, Romana, Smith, Jessica, Galloway, Stacey, Haywood, Natalie J, Soomro, Taha, Griffin, Kathryn J, Wheatcroft, Stephen B, Yuldasheva, Nadira Y, Beech, David J, Carmeliet, Peter, Kearney, Mark T, and Cubbon, Richard M

Subjects
INSULIN receptors, VASCULAR endothelial growth factors, NEOVASCULARIZATION, NITRIC-oxide synthases, SPROUTS
Abstract

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr+/- mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2. [ABSTRACT FROM AUTHOR]

Published
2021
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46. Endothelial IGF‐1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

Author

Haywood, Natalie J, Luk, Cheukyau, Bridge, Katherine I, Drozd, Michael, Makava, Natallia, Skromna, Anna, Maccannell, Amanda, Ozber, Claire H, Warmke, Nele, Wilkinson, Chloe G, Watt, Nicole T, Koch‐Paszkowski, Joanna, Teh, Irvin, Boyle, Jordan H, Smart, Sean, Schneider, Jurgen E, Yuldasheva, Nadira Y, Roberts, Lee D, Beech, David J, and Sukumar, Piruthivi

Abstract

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin‐like growth factor‐1 (IGF‐1) and its receptor (IGF‐1R) are critical for coupling nutritional status and cellular growth; IGF‐1R is expressed in multiple cell types including EC. The role of ECIGF‐1R in the response to nutritional obesity is unexplored. To examine this, we use gene‐modified mice with EC‐specific overexpression of human IGF‐1R (hIGFREO) and their wild‐type littermates. After high‐fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad‐spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF‐1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet‐induced obesity, as a result of an altered gut microbiota. SYNOPSIS: It remained unclear if gut endothelial cells can directly influence the microbiota. Here, endothelial specific over‐expression of IGF‐1R is shown to promote advantageous remodelling of the gut microbiota upon high fat diet, which protects against the development of obesity. Mice overexpressing insulin like growth factor‐1 receptors in the endothelium (hIGFREO) are protected against obesity.Protection against obesity is in part due to remodelling of the intestinal microbiota due to endothelium‐enterocyte crosstalk.Altered microbial diversity in the gut leads to a relative increase in the beneficial genus Akkermansia.Microbiota depletion using broad‐spectrum antibiotics attenuates advantageous metabolic phenotypes of hIGFREO mice. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Sergey Nejentsev [1, 57]; Joanna M. M. Howson (corresponding author) [1, 57]; Neil M. Walker [1]; Jeffrey Szeszko [1]; Sarah F. Field [1]; Helen E. Stevens [1]; Pamela Reynolds [...]

Published
2007
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48. Effects of obesity on insulin: insulin-like growth factor 1 hybrid receptor expression and Akt phosphorylation in conduit and resistance arteries.

Author

Mughal, Romana S, Bridge, Katherine, Buza, Irma, Slaaby, Rita, Worm, Jesper, Klitgaard-Povlsen, Gro, Hvid, Henning, Schiødt, Marianne, Cubbon, Richard, Yuldasheva, Nadira, Skromna, Anna, Makava, Natallia, Skytte-Olsen, Grith, and Kearney, Mark T

Abstract

Insulin and insulin-like growth factor-1 stimulate specific responses in arteries, which may be disrupted by diet-induced obesity. We examined (1) temporal effects of high-fat diet compared to low-fat diet in mice on insulin receptor, insulin-like growth factor-1 receptor, insulin receptor/insulin-like growth factor-1 receptor hybrid receptor expression and insulin/insulin-like growth factor-1-mediated Akt phosphorylation in aorta; and (2) effects of high-fat diet on insulin and insulin-like growth factor-1-mediated Akt phosphorylation and vascular tone in resistance arteries. Medium-term high-fat diet (5 weeks) decreased insulin-like growth factor-1 receptor expression and increased hybrid expression (~30%) only. After long-term (16 weeks) high-fat diet, insulin receptor expression was reduced by ~30%, insulin-like growth factor-1 receptor expression decreased a further ~40% and hybrid expression increased a further ~60%. Independent correlates of hybrid receptor expression were high-fat diet, duration of high-fat diet and plasma insulin-like growth factor-1 (all p < 0.05). In aorta, insulin was a more potent activator of Akt than insulin-like growth factor-1, whereas in resistance arteries, insulin-like growth factor-1 was more potent than insulin. High-fat diet blunted insulin-mediated vasorelaxation (p < 0.01) but had no effect on insulin-like growth factor-1-mediated vasorelaxation in resistance arteries. Our findings support the possibility that hybrid receptor level is influenced by nutritional and metabolic cues. Moreover, vessel-dependent effects of insulin and insulin-like growth factor-1 on vascular tone and Akt activation may have implications in treating obesity-related vascular disease. [ABSTRACT FROM AUTHOR]

Published
2019
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50. Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.

Author

Watt, Nicole T., Gage, Matthew C., Patel, Peysh A., Viswambharan, Hema, Sukumar, Piruthivi, Galloway, Stacey, Yuldasheva, Nadira Y., Imrie, Helen, Walker, Andrew M. N., Griffin, Kathryn J., Makava, Natalia, Skromna, Anna, Bridge, Katherine, Beech, David J., Schurmans, Stéphane, Wheatcroft, Stephen B., Kearney, Mark T., Cubbon, Richard M., and Walker, Andrew Mn

Subjects
HOMOLOGY (Biochemistry), INOSITOL phosphatase, LIPIDS, PHOSPHATIDYLINOSITOL 3-kinases, ENDOTHELIAL cells, ALLELES, SUPEROXIDES
Abstract

Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2Δ/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2Δ/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2Δ/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2Δ/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2Δ/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Δ/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Published
2017
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