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4. Integrating multiplex immunofluorescent and mass spectrometry imaging to map myeloid heterogeneity in its metabolic and cellular context

Author

Goossens, Pieter, Lu, Chang, Cao, Jianhua, Gijbels, Marion J., Karel, Joël M.H., Wijnands, Erwin, Claes, Britt S.R., Fazzi, Gregorio E., Hendriks, Tim F.E., Wouters, Kristiaan, Smirnov, Evgueni, van Zandvoort, Marc J.M., Balluff, Benjamin, Cuypers, Eva, Donners, Marjo M.P.C., Heeren, Ron M.A., and Biessen, Erik A.L.

Published
2022
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5. Association between Long-term Energy Balance-Related Factors and Survival in Colorectal Cancer Overall and by Metabolic Warburg-Subtypes.

Author

Offermans, Kelly, Jenniskens, Josien C. A., Simons, Colinda C. J. M., Samarska, Iryna, Fazzi, Gregorio E., Smits, Kim M., Schouten, Leo J., Weijenberg, Matty P., Grabsch, Heike I., and van den Brandt, Piet A.

Abstract

Background: Long-term energy balance-related factors (i.e., lifestyle and physiologic factors that influence the equilibrium between energy intake and energy expenditure over an extended period) such as body mass index (BMI) are linked to colorectal cancer risk, but their impact on colorectal cancer survival is unclear. We explored associations between these long-term energy balance-related factors and survival and examined potential differences across metabolic Warburg-subtypes. Methods: Associations between long-term energy balance-related factors and survival in the total series of patients with colorectal cancer (n = 2,347) obtained from the prospective Netherlands Cohort Study, as well as according to Warburg-subtype (Warburg-low: n = 652, Warburg-moderate: n = 802, Warburg-high: n = 797), were investigated using Cox regression analysis. Results: Among the long-term energy balance-related factors studied, only increasing prediagnostic BMI was associated with a borderline significant poorer overall survival in patients with colorectal cancer [HR5kg/m2, 1.07; 95% confidence interval (CI), 0.99-1.15]. Stratified analyses showed that prediagnostic weight gain (HR5kg, 1.04; 95% CI, 0.99-1.09) and potentially increased height (HR5cm, 1.04; 95% CI, 0.98-1.11) were associated with poor overall survival only in patients with Warburg-high colorectal cancer. Increasing prediagnostic BMI was associated with poor survival only in patients with Warburg-moderate colorectal cancer (colorectal cancer-specific: HR5kg/m2, 1.12; 95% CI, 0.96-1.32; overall: HR5kg/m2, 1.20; 95% CI, 1.05-1.36). No consistent patterns were observed across energy restriction proxies. Conclusions: Maintaining a healthy prediagnostic BMI may be beneficial for colorectal cancer survival. Moreover, associations between prediagnostic BMI, weight change, early-life energy restriction, height, and colorectal cancer survival differed according to Warburg-subtypes. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial

Author

Liu, Drolaiz H. W., primary, Kim, Young-Woo, additional, Sefcovicova, Nina, additional, Laye, Jon P., additional, Hewitt, Lindsay C., additional, Irvine, Andrew F., additional, Vromen, Vincent, additional, Janssen, Yannick, additional, Davarzani, Naser, additional, Fazzi, Gregorio E., additional, Jolani, Shahab, additional, Melotte, Veerle, additional, Magee, Derek R., additional, Kook, Myeong-Cherl, additional, Kim, Hyunki, additional, Langer, Rupert, additional, Cheong, Jae-Ho, additional, and Grabsch, Heike I., additional

Published
2023
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8. Energy balance‐related factors in childhood and adolescence and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status

Author

Jenniskens, Josien C. A., primary, Offermans, Kelly, additional, Simons, Colinda C. J. M., additional, Samarska, Iryna, additional, Fazzi, Gregorio E., additional, van der Meer, Jaleesa R. M., additional, Smits, Kim M., additional, Schouten, Leo J., additional, Weijenberg, Matty P., additional, Grabsch, Heike I., additional, and van den Brandt, Piet A., additional

Published
2022
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9. Association between mutational subgroups, Warburg‐subtypes, and survival in patients with colorectal cancer

Author

Offermans, Kelly, primary, Jenniskens, Josien C. A., additional, Simons, Colinda C. J. M., additional, Samarska, Iryna, additional, Fazzi, Gregorio E., additional, van der Meer, Jaleesa R. M., additional, Smits, Kim M., additional, Schouten, Leo J., additional, Weijenberg, Matty P., additional, Grabsch, Heike I., additional, and van den Brandt, Piet A., additional

Published
2022
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10. Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect

Author

Jenniskens, Josien C A, Jenniskens, Josien C A, Offermans, Kelly, Simons, Colinda C J M, Samarska, Iryna, Fazzi, Gregorio E, Smits, Kim M, Schouten, Leo J, Weijenberg, Matty P, Grabsch, Heike I, van den Brandt, Piet A, Jenniskens, Josien C A, Jenniskens, Josien C A, Offermans, Kelly, Simons, Colinda C J M, Samarska, Iryna, Fazzi, Gregorio E, Smits, Kim M, Schouten, Leo J, Weijenberg, Matty P, Grabsch, Heike I, and van den Brandt, Piet A

Abstract

BACKGROUND: Energy balance-related factors [body mass index (BMI), waist circumference, physical activity] have been associated with colorectal cancer risk. Warburg effect activation via PI3K/Akt signaling is one of the proposed mechanisms. We investigated whether energy balance-related factors were associated with risk of Warburg subtypes in colorectal cancer.METHODS: We investigated this using immunohistochemistry for six proteins involved in the Warburg effect (LDHA, GLUT1, MCT4, PKM2, P53, PTEN) on tissue microarrays of 2,399 incident colorectal cancer cases from the prospective Netherlands Cohort Study (n total = 120,852; n subcohort = 5,000; aged 55-69 in 1986; 20.3 years follow-up). Data analyses included 3,911 subcohort members and 1,972 colorectal cancer cases with complete covariate data. Expression levels of all proteins were combined into a pathway-based sum score and categorized into three "Warburg subtypes" (Warburg-low/moderate/high). Multivariable Cox regression analyses were used to estimate associations of BMI, clothing size (waist circumference proxy), and physical activity with Warburg subtypes in colorectal cancer.RESULTS: BMI and clothing size were positively associated with Warburg-moderate and Warburg-high colon cancer risk in men (P heterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (P heterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P heterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (P heterogeneity = 0.089).CONCLUSIONS: The Warburg effect might be involved in associations between adiposity and colon cancer risk, though additional mechanisms could be at play in women as well. The inverse association between physical activity and colon cancer might be explained by mechanisms other than the Warburg effect.IMPAC

Published
2022

11. Energy Balance–Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect

Author

Jenniskens, Josien C.A., primary, Offermans, Kelly, additional, Simons, Colinda C.J.M., additional, Samarska, Iryna, additional, Fazzi, Gregorio E., additional, Smits, Kim M., additional, Schouten, Leo J., additional, Weijenberg, Matty P., additional, Grabsch, Heike I., additional, and van den Brandt, Piet A., additional

Published
2022
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12. Energy balance‐related factors in childhood and adolescence and risk of colorectal cancer expressing different levels of proteins involved in the Warburg‐effect

Author

Jenniskens, Josien C. A., primary, Offermans, Kelly, additional, Simons, Colinda C. J. M., additional, Samarska, Iryna, additional, Fazzi, Gregorio E., additional, Smits, Kim M., additional, Schouten, Leo J., additional, Weijenberg, Matty P., additional, Grabsch, Heike I., additional, and Brandt, Piet A., additional

Published
2022
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13. Association between mutational subgroups, Warburg‐subtypes, and survival in patients with colorectal cancer.

Author

Offermans, Kelly, Jenniskens, Josien C. A., Simons, Colinda C. J. M., Samarska, Iryna, Fazzi, Gregorio E., van der Meer, Jaleesa R. M., Smits, Kim M., Schouten, Leo J., Weijenberg, Matty P., Grabsch, Heike I., and van den Brandt, Piet A.

Subjects
COLORECTAL cancer, OVERALL survival, CANCER patients, SOMATIC mutation, BRAF genes
Abstract

Background: Previous research suggests that Warburg‐subtypes are related to potentially important survival differences in colorectal cancer (CRC) patients. In the present study, we investigated whether mutational subgroups based on somatic mutations in RAS, BRAF, PIK3CA, and MET, which are known to promote the Warburg‐effect, as well as mismatch repair (MMR) status, hold prognostic value in CRC. In addition, we investigated whether Warburg‐subtypes provide additional prognostic information, independent of known prognostic factors like TNM stage. Methods: CRC patients (n = 2344) from the prospective Netherlands Cohort Study (NLCS) were classified into eight mutually exclusive mutational subgroups, based on observed mutations in RAS, BRAF, PIK3CA, and MET, and MMR status: All‐wild‐type + MMRproficient, KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, BRAFmut + MMRdeficient, other + MMRproficient, and other + MMRdeficient. Kaplan–Meier curves and Cox regression models were used to investigate associations between mutational subgroups and survival, as well as associations between our previously established Warburg‐subtypes and survival within these mutational subgroups. Results: Compared to patients with all‐wild‐type + MMRproficient CRC, patients with KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, or other + MMRproficient CRC had a statistically significant worse survival (HRCRC‐specific ranged from 1.29 to 1.88). In contrast, patients with other + MMRdeficient CRC had the most favorable survival (HRCRC‐specific 0.48). No statistically significant survival differences were observed for the Warburg‐subtypes within mutational subgroups. Conclusion: Our results highlight the prognostic potential of mutational subgroups in CRC. Warburg‐subtypes did not provide additional prognostic information within these mutational subgroups. Future larger‐scale prospective studies are necessary to validate our findings and to examine the potential clinical utility of CRC subtyping based on mutational subgroups. [ABSTRACT FROM AUTHOR]

Published
2023
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17. Integrative multiomics analysis of human atherosclerosis reveals a serum response factor‐driven network associated with intraplaque hemorrhage

Author

Jin, Han, primary, Goossens, Pieter, additional, Juhasz, Peter, additional, Eijgelaar, Wouter, additional, Manca, Marco, additional, Karel, Joël M. H., additional, Smirnov, Evgueni, additional, Sikkink, Cornelis J. J. M., additional, Mees, Barend M. E., additional, Waring, Olivia, additional, van Kuijk, Kim, additional, Fazzi, Gregorio E., additional, Gijbels, Marion J. J., additional, Kutmon, Martina, additional, Evelo, Chris T. A., additional, Hedin, Ulf, additional, Daemen, Mat J. A. P., additional, Sluimer, Judith C., additional, Matic, Ljubica, additional, and Biessen, Erik A. L., additional

Published
2021
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18. Expression of proteins associated with the Warburg‐effect and survival in colorectal cancer.

Author

Offermans, Kelly, Jenniskens, Josien CA, Simons, Colinda CJM, Samarska, Iryna, Fazzi, Gregorio E, Smits, Kim M, Schouten, Leo J, Weijenberg, Matty P, Grabsch, Heike I, and van den Brandt, Piet A

Subjects
PROTEIN expression, COLORECTAL cancer, RECTAL cancer, OVERALL survival, PROGNOSIS
Abstract

Previous research has suggested that the expression of proteins related to the Warburg effect may have prognostic value in colorectal cancer (CRC), but results remain inconsistent. Our objective was to investigate the relationship between Warburg‐subtypes and patient survival in a large population‐based series of CRC patients. In the present study, we investigated the expression of six proteins related to the Warburg effect (LDHA, GLUT1, MCT4, PKM2, p53, PTEN) by immunohistochemistry on tissue microarrays (TMAs) from 2,399 incident CRC patients from the prospective Netherlands Cohort Study. Expression levels of the six proteins were combined into a pathway‐based sum‐score and patients were categorised into three Warburg‐subtypes (low/moderate/high). The associations between Warburg‐subtypes and CRC‐specific and overall survival were investigated using Kaplan–Meier curves and Cox regression models. CRC patients were classified as Warburg‐low (n = 695, 29.0%), Warburg‐moderate (n = 858, 35.8%) or Warburg‐high (n = 841, 35.1%). Patients with Warburg‐high CRC had the poorest CRC‐specific [hazard ratio (HR) 1.17; 95% CI 1.00–1.38] and overall survival (HR 1.19; 95% CI 1.05–1.35), independent of known prognostic factors. In stratified analyses, this was particularly true for patients with tumour‐node‐metastasis (TNM) stage III CRC (HRCRC‐specific 1.45; 95% CI 1.10–1.92 and HRoverall 1.47; 95% CI 1.15–1.87), and cancers located in the rectum (HRoverall 1.56; 95% CI 1.15–2.13). To our knowledge, this is the first study to identify the prognostic value of immunohistochemistry‐based Warburg‐subtypes in CRC. Our data suggest that Warburg‐subtypes are related to potentially important differences in CRC survival. Further research is required to validate our findings and to investigate the potential clinical utility of these Warburg‐subtypes in CRC. [ABSTRACT FROM AUTHOR]

Published
2022
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20. Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: A large multi-centre study

Author

Hewitt, Lindsay C., Inam, Imran Z., Saito, Yuichi, Yoshikawa, Takaki, Quaas, Alexander, Hölscher, Arnulf H., Bollschweiler, Elfriede, Fazzi, Gregorio E., Melotte, Veerle, Langley, Ruth Elizabeth, Nankivell, Matthew, Cunningham, David, Allum, William, Hutchins, Gordon G., Grabsch, Heike Irmgard, Clinical Genetics, Promovendi ODB, Pathologie, and RS: GROW - R2 - Basic and Translational Cancer Biology

Subjects
HIGH-INCIDENCE AREA, Epsteine-Barr virus, Oesophageal cancer, DNA mismatch repair, COLON-CANCER, NONPOLYPOSIS COLORECTAL-CANCER, RANDOMIZED PHASE-3 TRIAL, OPEN-LABEL, PD-1 BLOCKADE, DOUBLE-BLIND, MICROSATELLITE-INSTABILITY, SDG 3 - Good Health and Well-being, hemic and lymphatic diseases, Microsatellite instability, ddc:610, SQUAMOUS-CELL CARCINOMA, CLINICAL-PRACTICE GUIDELINES, Gastric cancer
Abstract

Background: Oesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/ or EpsteineBarr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC. Methods: EBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC. Results: Frequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022). Conclusions: This is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients. (C) 2018 The Authors. Published by Elsevier Ltd.

Published
2018

21. Pollination ofSpeckliniaby nectar-feedingDrosophila: the first reported case of a deceptive syndrome employing aggregation pheromones in Orchidaceae

Author

Karremans, Adam P., primary, Pupulin, Franco, additional, Grimaldi, David, additional, Beentjes, Kevin K., additional, Butôt, Roland, additional, Fazzi, Gregorio E., additional, Kaspers, Karsten, additional, Kruizinga, Jaco, additional, Roessingh, Peter, additional, Smets, Erik F., additional, and Gravendeel, Barbara, additional

Published
2015
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22. Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT1-Receptor Mediated Immune Response

Author

Heijnen, Bart F. J., primary, Nelissen, Jelly, additional, van Essen, Helma, additional, Fazzi, Gregorio E., additional, Cohen Tervaert, Jan W., additional, Peutz-Kootstra, Carine J., additional, Mullins, John J., additional, Schalkwijk, Casper G., additional, Janssen, Ben J. A., additional, and Struijker-Boudier, Harry AJ., additional

Published
2013
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23. Reduced responsiveness of rat mesenteric resistance artery smooth muscle to phenylephrine and calcium following myocardial infarction

Author

Stassen, Frank R M, Willemsen, Maurice J J M F, Janssen, Ger M J, Fazzi, Gregorio E, Schiffers, Paul M H, Smits, Jos F M, and De Mey, Jo G R

Subjects
Male, Phenylephrine, Receptors, Adrenergic, alpha-1, Papers, cardiovascular system, Myocardial Infarction, Animals, Calcium, Vascular Resistance, Rats, Wistar, Mesenteric Arteries, Muscle Contraction, Rats
Abstract

1. We evaluated responses of peripheral resistance arterial smooth muscle to alpha 1-adrenoceptor stimulation in a rat model of heart failure in relation to neurohumoral changes, wall structure, receptor density and cellular calcium handling. 2. Plasma samples and third order mesenteric artery side-branches were obtained from Wistar rats after induction of left ventricular infarction (M1) or sham surgery. Vessels were denuded of endothelium, sympathectomized, depleted of neuropeptides, and mounted in a myograph for recording of isometric force development in response to calcium, agonist and high potassium. Also, the morphology of these preparations was determined. Separate vessel segments were used in radioligand binding assays with [1H]-prazosin. 3. At 1 week after MI, circulating plasma levels of adrenaline, angiotensin II, atrial natriuretic factor (ANF) and vasopressin were significantly elevated. At 5 weeks only a significant elevation of ANF persisted. 4. At 5 weeks after MI, the structure of the vessels and responsiveness to high potassium or Bay K 8466 (10(6) mol l-1) were not modified. Yet, at this stage, sensitivity to phenylephrine was increased (pD2: 6.24 +/- 0.04 vs 5.98 +/- 0.04 for controls) while maximal contractile responses to phenylephrine in the presence of 2.5 mmol l-1 calcium (2.26 +/- 0.28 vs 3.53 +/- 0.34 N m-1) and the sensitivity to calcium in the presence of phenylephrine (pD2: 2.81 +/- 0.22 vs 3.74 +/- 0.16) were reduced. Responses to the agonist in calcium-free solution and the calcium sensitivity in the presence of 125 mmol l-1 potassium or of phorbol myristate acetate (PMA, 10(-6) mol l-1) were not altered. 5. At 5 weeks after MI, the density of prazosin binding sites was not reduced (4.04 +/- 1.40 vs 2.29 +/- 0.21 fmol microgram-1 DNA in controls). 6. In conclusion, myocardial infarction leads in the rat to a reduction of contractile responses of mesenteric resistance arterial smooth muscle to alpha 1-adrenoceptor stimulation. This seems to involve impaired agonist-stimulated calcium influx.

Published
1997

25. Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

Author

Storkebaum, Erik, primary, Ruiz de Almodovar, Carmen, additional, Meens, Merlijn, additional, Zacchigna, Serena, additional, Mazzone, Massimiliano, additional, Vanhoutte, Greet, additional, Vinckier, Stefan, additional, Miskiewicz, Katarzyna, additional, Poesen, Koen, additional, Lambrechts, Diether, additional, Janssen, Ger M.J., additional, Fazzi, Gregorio E., additional, Verstreken, Patrik, additional, Haigh, Jody, additional, Schiffers, Paul M., additional, Rohrer, Hermann, additional, Van der Linden, Annemie, additional, De Mey, Jo G.R., additional, and Carmeliet, Peter, additional

Published
2010
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37. Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT1-Receptor Mediated Immune Response.

Author

Heijnen, Bart F. J., Nelissen, Jelly, van Essen, Helma, Fazzi, Gregorio E., Cohen Tervaert, Jan W., Peutz-Kootstra, Carine J., Mullins, John J., Schalkwijk, Casper G., Janssen, Ben J. A., and Struijker-Boudier, Harry AJ.

Subjects
KIDNEY diseases, RENIN-angiotensin system, ANGIOTENSIN receptors, IMMUNE response, BLOOD pressure, KIDNEY function tests, LABORATORY rats
Abstract

Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4–8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4–8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension. [ABSTRACT FROM AUTHOR]

Published
2013
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42. Twenty-four-hour exposure to altered blood flow modifies endothelial Ca2+-activated K+ channels in rat mesenteric arteries.

Author

Hilgers, Rob H P, Janssen, Ger M J, Fazzi, Gregorio E, and De Mey, Jo G R

Abstract

We tested the hypothesis that changes in arterial blood flow modify the function of endothelial Ca2+-activated K+ channels [calcium-activated K+ channel (K(Ca)), small-conductance calcium-activated K+ channel (SK3), and intermediate calcium-activated K+ channel (IK1)] before arterial structural remodeling. In rats, mesenteric arteries were exposed to increased [+90%, high flow (HF)] or reduced blood flow [-90%, low flow (LF)] and analyzed 24 h later. There were no detectable changes in arterial structure or in expression level of endothelial nitric-oxide synthase, SK3, or IK1. Arterial relaxing responses to acetylcholine and 3-oxime-6,7-dichlore-1H-indole-2,3-dione (NS309; activator of SK3 and IK1) were measured in the absence and presence of endothelium, NO, and prostanoid blockers, and 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo [b,n] [1,5,12,16]tetraazacyclotricosine-5,13-diium dibromide (UCL 1684; inhibitor of SK3) or 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; inhibitor of IK1). In LF arteries, endothelium-dependent relaxation was markedly reduced, due to a reduction in the endothelium-derived hyperpolarizing factor (EDHF) response. In HF arteries, the balance between the NO/prostanoid versus EDHF response was unaltered. However, the contribution of IK1 to the EDHF response was enhanced, as indicated by a larger effect of TRAM-34 and a larger residual NS309-induced relaxation in the presence of UCL 1684. Reduction of blood flow selectively blunts EDHF relaxation in resistance arteries through inhibition of the function of K(Ca) channels. An increase in blood flow leads to a more prominent role of IK1 channels in this relaxation.

Published
2010
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43. Functional antagonism between endogenous neuropeptide Y and calcitonin gene-related peptide in mesenteric resistance arteries.

Author

De Mey, Jo G R, Megens, Remco, and Fazzi, Gregorio E

Abstract

To test the hypothesis that endogenous neuropeptide Y (NPY) counteracts the vasodilator effects of calcitonin gene-related peptide (CGRP), we used isolated mesenteric resistance arteries of rats and mice. With immunohistochemistry, we observed CGRP-containing fibers along and in the vicinity of a subset of NPY- or tyrosine hydroxylase-immunoreactive fibers. The CGRP1 receptor component calcitonin-related-like receptor was expressed by periarterial nerves and smooth muscle cells, whereas receptor activity-modifying protein 1 was observed primarily on the smooth muscle. In organ chambers, exogenous CGRP caused relaxations that were reversed by exogenous NPY. The effects were inhibited by 1-piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]-carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)-methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS, a CGRP1 receptor antagonist; pK(B) = 8.54 +/- 0.52) and (R)-NZ-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide (BIBP3226, a Y1 antagonist; pK(B) = 7.00 +/- 0.49), respectively. Pretreatment with capsaicin (1 muM; 20 min) and the presence of BIBN4096BS (20 nM) increased contractile responses to K(+) (20-40 mM) and electrical field stimulation (EFS; 1-32 Hz). NPY increased contractile responses to K(+) and BIBP3226 (400 nM) reduced contractile responses to EFS. These effects were inhibited by capsaicin and BIBN4096BS, respectively. Furthermore, the relaxing effect of exogenous CGRP (10 nM) during phenylephrine-induced contraction (30 muM) was reversed by EFS, and this effect was reduced in the presence of BIBP3226. We confirmed that bioactive concentrations of endogenous CGRP and NPY can be released from periarterial sensory-motor and sympathetic nerves, respectively, and we demonstrate for the first time functional antagonism between endogenous NPY and CGRP at the level of the smooth muscle.

Published
2008
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44. Seroreactivity of patients with Crohn's disease with lymph nodes of primed nude mice is independent of the tissue used for priming

Author

Walvoort, Hendrik C., Fazzi, Gregorio E., and Peña, A.Salvador

Abstract

Athymic nude mice, injected with a cell-free filtrate of intestinal tissue from patients with Crohn's disease, have been shown to express antigens in their lymph nodes to which sera from patients with Crohn's disease contain antibodies. In the present study, immune reactivity was assessed with a histochemical indirect immunoperoxidase assay on paraplast-embedded tissue sections. The reactive lymph node cells were identified as sinus macrophages. We confirmed earlier findings of immunofluorescence studies that the reaction showed some antibody specificity, the proportion of patients with Crohn's disease who were positive (84%) being higher than of patients with ulcerative colitis (29%). However, reactivity of Crohn's disease sera was found to be antigen nonspecific, as it was equally observed with lymph nodes of mice primed with saline or with homogenates from patients with ulcerative colitis, diverticulitis, or volvulus. Hence, this nude mouse model does not seem appropriate to identify a transmissible etiology of Crohn's disease.

Published
1989
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45. In vivo DNA synthesis is not uniformly increased in arterial smooth muscle of young spontaneously hypertensive rats

Author

Mey, Jo G.R. De, Daemen, Mat J.A.P., Boonen, Harrie C.M., Bosman, Fre T., Dijkstra, Ellis H., Fazzi, Gregorio E., Janssen, Ger M.J., Schiffers, Paul M.H., Struyker-Boudier, Harry A.J., and Vrijdag, Marian J.J.F.

Abstract

We compared the distribution of DNA synthesis over the arterial tree of young normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with marginally elevated blood pressure. Six-week-old male SHR and WKY rats were therefore infused with 5-bromo-2'-deoxyuridine (BrdUrd) for 2 days and the nuclear incorporation of the thymidine analogue in the media of various arteries was determined by immunohistochemistry. In WKY rats, 2.5 of the arterial smooth muscle nuclei in elastic, muscular and resistance arteries incorporated BrdUrd. In SHR, DNA synthesis was more marked in large arteries than in resistance arteries. It was in addition significantly larger in the aorta, superior mesenteric, renal and femoral arteries of the SHR than in those of the WKY rats. However, nuclear incorporation of BrdUrd in vivo did not differ between SHR and WKY rats in aortic endothelium, carotid arterial smooth muscle, nor in mesenteric or renal resistance arteries. Between 6 and 20 weeks of age, the number of nuclear profiles per media cross-section did not increase in large arteries of WKY rats and SHR. During this period of time, however, carotid artery and thoracic aorta weight and DNA content increased. SHR large arteries gained more DNA than those of WKY rats. These data indicate that DNA synthesis is uniformly distributed over the arterial system in young WKY rats and that DNA synthesis is elevated in the smooth muscle of large arteries of 6-week-old SHR but not in their resistance arteries.

Published
1991

46. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

Author

Jody J. Haigh, Patrik Verstreken, Ger M.J. Janssen, Diether Lambrechts, Peter Carmeliet, Paul M. H. Schiffers, Greet Vanhoutte, Massimiliano Mazzone, Carmen Ruiz de Almodovar, Hermann Rohrer, Jo G. R. De Mey, Gregorio E. Fazzi, Koen Poesen, Stefan Vinckier, Merlijn J. Meens, Annemie Van der Linden, Serena Zacchigna, Katarzyna Miskiewicz, Erik Storkebaum, Promovendi CD, Ondersteunend personeel CD, Farmacologie & Toxicologie, Bedrijfsbureau CD, RS: CARIM School for Cardiovascular Diseases, Storkebaum, Erik, Ruiz De Almodovar, Carmen, Meens, Merlijn, Zacchigna, Serena, Mazzone, Massimiliano, Vanhoutte, Greet, Vinckier, Stefan, Miskiewicz, Katarzyna, Poesen, Koen, Lambrechts, Diether, Janssen, Ger M. J., Fazzi, Gregorio E., Verstreken, Patrik, Haigh, Jody, Schiffers, Paul M., Rohrer, Hermann, Van Der Linden, Annemie, De Mey, Jo G. R., and Carmeliet, Peter

Subjects
Vascular Endothelial Growth Factor A, SYMPATHETIC-NERVOUS-SYSTEM, Vascular smooth muscle, muscle, SMOOTH-MUSCLE-CELLS, Gene Expression, Transgenic, Muscle, Smooth, Vascular, Neuroeffector junction, arteries, chemistry.chemical_compound, Mesenteric Arterie, Mice, Cardiovascular Disease, vasoconstriction, vascular endothelial growth factor, Medicine (all), nervous system, Gene Transfer Techniques, arterie, Autonomic Nervous System Disease, MESENTERIC-ARTERIES, VEGF, Common, Mesenteric Arteries, Vascular endothelial growth factor B, Vascular endothelial growth factor, Vascular endothelial growth factor A, DIFFERENTIATION, medicine.anatomical_structure, Lac Operon, Cardiovascular Diseases, SURVIVAL, Smooth, Cardiology and Cardiovascular Medicine, smooth, Signal Transduction, EXPRESSION, medicine.medical_specialty, Neuroeffector, Carotid Artery, Common, Mice, Transgenic, RATS, Internal medicine, Vascular, Physiology (medical), muscle, smooth, medicine, Animals, Autonomic Nervous System Diseases, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2, Vascular Resistance, Vasoconstriction, ERYTHRODYSESTHESIA, RECEPTOR, business.industry, Animal, Biology and Life Sciences, Kinase insert domain receptor, Gene Transfer Technique, Endocrinology, chemistry, Vascular resistance, Human medicine, Carotid Artery, business
Abstract

Background— Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results— Here, we report that VEGF ∂/∂ mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions— These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

Published
2010

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