36 results on '"Fazzi, Gregorio E."'
Search Results
2. Relationship between the Warburg effect in tumour cells and the tumour microenvironment in colorectal cancer patients: Results from a large multicentre study
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Steeghs, Jorn P.J.M., Offermans, Kelly, Jenniskens, Josien C.A., Samarska, Iryna, Fazzi, Gregorio E., van den Brandt, Piet A., and Grabsch, Heike I.
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- 2023
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3. Energy balance-related factors and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status
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Jenniskens, Josien C. A., Offermans, Kelly, 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.
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- 2022
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4. Integrating multiplex immunofluorescent and mass spectrometry imaging to map myeloid heterogeneity in its metabolic and cellular context
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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.
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- 2022
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5. Pollination of Specklinia by nectar-feeding Drosophila : the first reported case of a deceptive syndrome employing aggregation pheromones in Orchidaceae
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Karremans, Adam P., Pupulin, Franco, Grimaldi, David, Beentjes, Kevin K., Butôt, Roland, Fazzi, Gregorio E., Kaspers, Karsten, Kruizinga, Jaco, Roessingh, Peter, Smets, Erik F., and Gravendeel, Barbara
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- 2015
6. Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial.
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Liu, Drolaiz H. W., Kim, Young-Woo, Sefcovicova, Nina, Laye, Jon P., Hewitt, Lindsay C., Irvine, Andrew F., Vromen, Vincent, Janssen, Yannick, Davarzani, Naser, Fazzi, Gregorio E., Jolani, Shahab, Melotte, Veerle, Magee, Derek R., Kook, Myeong-Cherl, Kim, Hyunki, Langer, Rupert, Cheong, Jae-Ho, and Grabsch, Heike I.
- Abstract
Background: Only a subset of gastric cancer (GC) patients with stage II–III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit. Methods: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S). The relationship between TIL density, disease-free survival (DFS) and clinicopathological variables was analysed. Results: YCC S patients and CLASSIC S patients with high TIL density had longer DFS than S patients with low TIL density (P = 0.007 and P = 0.013, respectively). Furthermore, CLASSIC patients with low TIL density had longer DFS if treated with S + C compared to S (P = 0.003). No significant relationship of TIL density with other clinicopathological variables was found. Conclusion: This is the first study to suggest TIL density automatically quantified in routine HE stained tissue sections as a novel, clinically useful biomarker to identify stage II–III GC patients deriving benefit from adjuvant chemotherapy. Validation of our results in a prospective study is warranted. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Association between mutational subgroups, Warburg‐subtypes, and survival in patients with colorectal cancer.
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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.
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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]
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- 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.
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Jenniskens, Josien C. A., Offermans, Kelly, 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.
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- 2022
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9. Energy balance‐related factors in childhood and adolescence and risk of colorectal cancer expressing different levels of proteins involved in the Warburg‐effect.
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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.
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COLORECTAL cancer ,COLON cancer ,DISEASE risk factors ,CANCER patients ,RECTAL cancer - Abstract
Early‐life (childhood to adolescence) energy balance‐related factors (height, energy restriction, BMI) have been associated with adult colorectal cancer (CRC) risk. Warburg‐effect activation via PI3K/Akt‐signaling might explain this link. We investigated whether early‐life energy balance‐related factors were associated with risk of Warburg‐subtypes in CRC. We used immunohistochemistry for six proteins involved in the Warburg‐effect (LDHA, GLUT1, MCT4, PKM2, P53, and PTEN) on tissue microarrays of 2399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS). 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 height, energy restriction proxies (exposure to Dutch Hunger Winter; Second World War [WWII]; Economic Depression) and adolescent BMI with Warburg‐subtypes in CRC. Height was positively associated with colon cancer in men, regardless of Warburg‐subtypes, and with Warburg‐low colon and Warburg‐moderate rectal cancer in women. Energy restriction during the Dutch Hunger Winter was inversely associated with colon cancer in men, regardless of Warburg‐subtypes. In women, energy restriction during the Hunger Winter and WWII was inversely associated with Warburg‐low colon cancer, whereas energy restriction during the Economic Depression was positively associated with Warburg‐high colon cancer. Adolescent BMI was positively associated with Warburg‐high colon cancer in men, and Warburg‐moderate rectal cancer in women. In conclusion, the Warburg‐effect seems to be involved in associations of adolescent BMI with colon cancer in men, and of energy restriction during the Economic Depression with colon cancer in women. Further research is needed to validate these results. [ABSTRACT FROM AUTHOR]
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- 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.
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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; nsubcohort = 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 (Pheterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (Pheterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (Pheterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (Pheterogeneity = 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. [ABSTRACT FROM AUTHOR]- Published
- 2022
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11. Expression of proteins associated with the Warburg‐effect and survival in colorectal cancer.
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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
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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]
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- 2022
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12. Validity and Reproducibility of Immunohistochemical Scoring by Trained Non-Pathologists on Tissue Microarrays.
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Jenniskens, Josien C. A., Offermans, Kelly, Samarska, Iryna, Fazzi, Gregorio E., Simons, Colinda C. J. M., Smits, Kim M., Schouten, Leo J., Weijenberg, Matty P., van den Brandt, Piet A., and Grabsch, Heike I.
- Abstract
Background: Scoring of immunohistochemistry (IHC) staining is often done by non-pathologists, especially in large-scale tissue microarray (TMA)-based studies. Studies on the validity and reproducibility of scoring results from non-pathologists are limited. Therefore, our main aim was to assess interobserver agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localization (nucleus/membrane/cytoplasm). Methods: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyze interobserver and intraobserver agreement for 6,249 TMA cores from a colorectal cancer series. Results: Interobserver agreement between non-pathologists (independently scored) and the histopathologist was "substantial" for nuclear and membranous IHC markers (K
range = 0.67-0.75 and Krange = 0.61-0.69, respectively), and "moderate" for the cytoplasmic IHC marker (Krange = 0.43-0.57). Scores of the three non-pathologists were also combined into a "combination score" (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (Knuclear = 0.74; Kmembranous = 0.73; Kcytopasmic = 0.57). Interobserver agreement between non-pathologists was "substantial" (Knuclear = 0.78; Kmembranous = 0.72; Kcytopasmic = 0.61). Intraobserver agreement of non-pathologists was "substantial" to "almost perfect" (Knuclear ,range = 0.83-0.87; Kmembranous ,range = 0.75-0.82; Kcytopasmic = 0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. Conclusions: This study shows that adequately trained non-pathologists are able to generate reproducible IHC scoring results, that are similar to those of an experienced histopathologist. A combination score of at least two non-pathologists yielded optimal results. [ABSTRACT FROM AUTHOR]- Published
- 2021
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13. Role of the Rhoa/Rho Kinase System in Flow-Related Remodeling of Rat Mesenteric Small Arteries in Vivo
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Wesselman, Jos P.M., Kuijs, Robin, Hermans, J. J. Rob, Janssen, Ger M.J., Fazzi, Gregorio E., van Essen, Helma, Evelo, Chris T.A., Struijker-Boudier, Harry A.J., and De Mey, Jo G.R.
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- 2004
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14. Integrative multiomics analysis of human atherosclerosis reveals a serum response factor‐driven network associated with intraplaque hemorrhage.
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Jin, Han, Goossens, Pieter, Juhasz, Peter, Eijgelaar, Wouter, Manca, Marco, Karel, Joël M. H., Smirnov, Evgueni, Sikkink, Cornelis J. J. M., Mees, Barend M. E., Waring, Olivia, van Kuijk, Kim, Fazzi, Gregorio E., Gijbels, Marion J. J., Kutmon, Martina, Evelo, Chris T. A., Hedin, Ulf, Daemen, Mat J. A. P., Sluimer, Judith C., Matic, Ljubica, and Biessen, Erik A. L.
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SERUM response factor ,ATHEROSCLEROSIS ,CARDIOVASCULAR diseases ,CHOLESTEROL metabolism ,HEMORRHAGE ,FOCAL adhesions ,CAROTID artery - Abstract
Background: While single‐omics analyses on human atherosclerotic plaque have been very useful to map stage‐ or disease‐related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale‐intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. Methods: In this study, we compared protein and gene makeup of low‐ versus high‐risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. Results: We identified a protein‐gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with αSMA−PDGFRα+ fibroblast‐like cell content (p = 2.4E‐05) and Arg1+ macrophage content (p = 2.2E‐04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia‐1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. Conclusions: In conclusion, our integrative omics study has identified an intraplaque hemorrhage‐associated cardiovascular signature that provides excellent stratification of low‐ from high‐risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF‐regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Reduced responsiveness of rat mesenteric resistance artery smooth muscle to phenylephrine and calcium following myocardial infarction
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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
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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.
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- 1997
16. Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT1-Receptor Mediated Immune Response.
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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.
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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 AT
1 -receptor (AT1 R) 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 AT1 R 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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17. Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats.
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Lemkens, Pieter, Nelissen, Jelly, Meens, Merlijn J P M T, Fazzi, Gregorio E, Janssen, Ger J M, Debets, Jacques J M, Janssen, Ben J A, Schiffers, Paul M H, and De Mey, Jo G R
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- 2012
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18. DNA synthesis in isolated arteries of normotensive and hypertensive rats.
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Schiffers, Paul M.H., Fazzi, Gregorio E., Janssen, Ger M.J., Uitendaal, Martin P., Struijker Boudier, Harry A.J., and De Mey, Jo G.R.
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- 1994
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19. In vivo DNA synthesis is not uniformly increased in arterial smooth muscle of young spontaneously hypertensive rats.
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De Mey, Jo G.R., 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., Vrijdag, Marian J.J.F., De Mey, J G, Daemen, M J, Boonen, H C, Bosman, F T, Dijkstra, E H, Fazzi, G E, Janssen, G M, Schiffers, P M, Struyker-Boudier, H A, and Vrijdag, M J
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- 1991
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20. Reduced responsiveness of rat mesenteric resistance artery smooth muscle to phenylephrine and calcium following myocardial infarction.
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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.
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- 1997
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21. Coronary Arterial Hyperreactivity and Mesenteric Arterial Hyporeactivity After Myocardial Infarction in the Rat.
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Stassen, Frank R. M., Fazzi, Gregorio E., Leenders, Peter J. A., Smits, Jos F. M., and De Mey, Jo G. R.
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- 1997
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22. Mesenteric Small Artery Changes After Vasoconstrictor Infusion in Young Rats.
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Boonen, Harrie C. M., Daemen, Mat J. A. P., Eerdmans, Pedro H. A., Fazzi, Gregorio E., van Kleef, Ellen M., Schiffers, Paul M. H., and De Mey, Jo G. R.
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- 1993
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23. DNA synthesis in isolated arteries. Kinetics and structural consequences.
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BOONEN, HARRIE C. M., SCHIFFERS, PAUL M. H., FAZZI, GREGORIO E., JANSSEN, GER M. J., DAEMEN, MAT J. A. P., and DE MEY, JO G. R.
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- 1991
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24. Angiotensin II Induces Media Hypertrophy and Hyperreactivity in Mesenteric but Not Epigastric Small Arteries of the Rat.
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Stassen, Frank R.M., Raat, Nicolaas J.H., Brouwers-Ceiler, Debbie L., Fazzi, Gregorio E., Smits, Jos F.M., and De Mey, Jo G.R.
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- 1997
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25. Growth Responses in Isolated Elastic, Muscular and Resistance-Sized Arterial Segments of the Rat.
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De Mey, Jo G.R., Uitendaal, Martin P., Boonen, Harrie C.M., Schiffers, Paul M.H., and Fazzi, Gregorio E.
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- 1991
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26. Seroreactivity of patients with Crohn's disease with lymph nodes of primed nude mice is independent of the tissue used for priming
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Walvoort, Hendrik C., Fazzi, Gregorio E., and Peña, A.Salvador
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- 1989
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27. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery
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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
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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.
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- 2010
28. Association between long-term energy balance-related factors and survival in colorectal cancer overall and by metabolic Warburg-subtypes.
- Author
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Offermans K, Jenniskens JC, Simons CC, Samarska I, Fazzi GE, Smits KM, Schouten LJ, Weijenberg MP, Grabsch HI, and van den Brandt PA
- Abstract
Background: Long-term energy balance-related factors (i.e. lifestyle and physiological factors that influence the equilibrium between energy intake and energy expenditure over an extended period) like body mass index (BMI) are linked to colorectal cancer (CRC) risk, but their impact on CRC 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 CRC patients (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 pre-diagnostic BMI was associated with a borderline significant poorer overall survival in CRC patients (HR5kg/m2 1.07; 95%CI 0.99-1.15). Stratified analyses showed that pre-diagnostic weight gain (HR5kg 1.06; 95%CI 1.00-1.12), 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 CRC. Increasing pre-diagnostic BMI was associated with poor survival only in patients with Warburg-moderate CRC (CRC-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 pre-diagnostic BMI may be beneficial for CRC survival. Moreover, associations between pre-diagnostic BMI, weight change, early-life energy restriction, height and CRC survival differed according to Warburg-subtype., Impact: Understanding the biological pathways involved in associations between energy balance-related factors and CRC survival could help refine prevention strategies in the future.
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- 2024
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29. Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response.
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Heijnen BF, Nelissen J, van Essen H, Fazzi GE, Cohen Tervaert JW, Peutz-Kootstra CJ, Mullins JJ, Schalkwijk CG, Janssen BJ, and Struijker-Boudier HA
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- Animals, Biomarkers metabolism, Hemodynamics drug effects, Hydralazine pharmacology, Hypertension immunology, Hypertension metabolism, Hypertension pathology, Hypertension physiopathology, Kidney drug effects, Kidney metabolism, Losartan pharmacology, Rats, Rats, Transgenic, Renin-Angiotensin System drug effects, T-Lymphocytes drug effects, T-Lymphocytes immunology, Time Factors, Kidney pathology, Kidney physiopathology, Receptor, Angiotensin, Type 1 metabolism, Renin-Angiotensin System immunology
- 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.
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- 2013
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30. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery.
- Author
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Storkebaum E, Ruiz de Almodovar C, Meens M, Zacchigna S, Mazzone M, Vanhoutte G, Vinckier S, Miskiewicz K, Poesen K, Lambrechts D, Janssen GM, Fazzi GE, Verstreken P, Haigh J, Schiffers PM, Rohrer H, Van der Linden A, De Mey JG, and Carmeliet P
- Subjects
- Animals, Autonomic Nervous System Diseases genetics, Cardiovascular Diseases genetics, Carotid Artery, Common innervation, Carotid Artery, Common physiology, Gene Expression physiology, Gene Transfer Techniques, Lac Operon, Mesenteric Arteries innervation, Mesenteric Arteries physiology, Mice, Mice, Transgenic, Muscle, Smooth, Vascular physiology, Signal Transduction physiology, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Autonomic Nervous System Diseases physiopathology, Cardiovascular Diseases physiopathology, Vascular Endothelial Growth Factor A genetics, Vascular Resistance physiology, Vasoconstriction physiology
- 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( partial differential/ partial differential) 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.
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- 2010
- Full Text
- View/download PDF
31. Twenty-four-hour exposure to altered blood flow modifies endothelial Ca2+-activated K+ channels in rat mesenteric arteries.
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Hilgers RH, Janssen GM, Fazzi GE, and De Mey JG
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- Acetylcholine pharmacology, Animals, Biological Factors physiology, Cyclooxygenase Inhibitors pharmacology, Endothelium, Vascular drug effects, Guanylate Cyclase pharmacology, Indoles pharmacology, Intermediate-Conductance Calcium-Activated Potassium Channels agonists, Intermediate-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Male, Mesenteric Arteries drug effects, Muscle Contraction, Muscle Relaxation, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiology, Nitric Oxide Synthase antagonists & inhibitors, Oximes pharmacology, Potassium Channels, Calcium-Activated agonists, Potassium Channels, Calcium-Activated antagonists & inhibitors, Rats, Rats, Inbred WKY, Receptors, Cytoplasmic and Nuclear pharmacology, Small-Conductance Calcium-Activated Potassium Channels, Soluble Guanylyl Cyclase, Splanchnic Circulation, Stress, Mechanical, Endothelium, Vascular metabolism, Intermediate-Conductance Calcium-Activated Potassium Channels biosynthesis, Mesenteric Arteries metabolism, Potassium Channels, Calcium-Activated biosynthesis
- 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.
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- 2010
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32. Calcitonin gene-related peptide selectively relaxes contractile responses to endothelin-1 in rat mesenteric resistance arteries.
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Meens MJ, Fazzi GE, van Zandvoort MA, and De Mey JG
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- Animals, Endothelin A Receptor Antagonists, Endothelin B Receptor Antagonists, Endothelin-1 antagonists & inhibitors, Male, Muscle, Smooth, Vascular physiology, Rats, Rats, Sprague-Dawley, Receptor, Endothelin A physiology, Receptor, Endothelin B physiology, Vasoconstriction physiology, Calcitonin Gene-Related Peptide physiology, Endothelin-1 physiology, Mesenteric Arteries physiology, Muscle Contraction physiology, Muscle Relaxation physiology, Vascular Resistance physiology, Vasodilation physiology
- Abstract
We tested the hypothesis that endothelin-1 (ET-1) modulates sensory-motor nervous arterial relaxation by prejunctional and postjunctional mechanisms. Isolated rat mesenteric resistance arteries were investigated with immunohistochemistry, wire-myography, and pharmacological tools. ET(A)- and ET(B)-receptors could be visualized on the endothelium and smooth muscle and on periarterial fibers containing calcitonin gene-related peptide (CGRP). Arterial contractile responses to ET-1 (0.25-16 nM) were not modified by blockade of ET(B)-receptors, NO-synthase, and cyclooxygenase or desensitization of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) with capsaicin. ET-1 reversed relaxing responses to CGRP in depolarized arteries. This effect was inhibited by ET(A)-antagonists. It was not selective because ET-1 also reversed relaxing responses to Na-nitroprusside (SNP) and because phenylephrine (PHE; 0.25-16 microM) similarly reversed relaxing responses to CGRP or SNP. Conversely, contractile responses to ET-1 were, compared with PHE, hypersensitive to the relaxing effects of the TRPV1-agonist capsaicin and to exogenous CGRP, but not to acetylcholine, forskolin, pinacidil, or SNP. In conclusion, ET-1 does not stimulate sensory-motor nervous arterial relaxation, but ET(A)-mediated arterial contractions are selectively sensitive to relaxation by the sensory neurotransmitter CGRP. This does not involve NO, cAMP, or ATP-sensitive K(+) channels.
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- 2009
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33. Functional antagonism between endogenous neuropeptide Y and calcitonin gene-related peptide in mesenteric resistance arteries.
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De Mey JG, Megens R, and Fazzi GE
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- Animals, Calcitonin Gene-Related Peptide analysis, Calcitonin Gene-Related Peptide pharmacology, Dose-Response Relationship, Drug, Male, Mesenteric Arteries chemistry, Mesenteric Arteries drug effects, Mice, Mice, Inbred C57BL, Neuropeptide Y analysis, Neuropeptide Y pharmacology, Rats, Rats, Wistar, Vasoconstriction drug effects, Vasoconstriction physiology, Vasomotor System chemistry, Vasomotor System drug effects, Vasomotor System physiology, Calcitonin Gene-Related Peptide physiology, Mesenteric Arteries physiology, Neuropeptide Y physiology
- 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.
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- 2008
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34. High sodium intake increases blood pressure and alters renal function in intrauterine growth-retarded rats.
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Sanders MW, Fazzi GE, Janssen GM, Blanco CE, and De Mey JG
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- Aging, Albuminuria chemically induced, Animals, Animals, Newborn, Dose-Response Relationship, Drug, Female, Glomerular Filtration Rate drug effects, Kidney physiopathology, Male, Rats, Rats, Wistar, Renal Circulation drug effects, Sodium, Dietary pharmacology, Blood Pressure drug effects, Fetal Growth Retardation physiopathology, Sodium, Dietary administration & dosage
- Abstract
A suboptimal fetal environment increases the risk to develop cardiovascular disease in the adult. We reported previously that intrauterine stress in response to reduced uteroplacental blood flow in the pregnant rat limits fetal growth and compromises renal development, leading to an altered renal function in the adult offspring. Here we tested the hypothesis that high dietary sodium intake in rats with impaired renal development attributable to intrauterine stress, results in increased blood pressure, altered renal function, and organ damage. In rats, intrauterine stress was induced by bilateral ligation of the uterine arteries at day 17 of pregnancy. At the age of 12 weeks, the offspring was given high-sodium drinking water (2% sodium chloride). At the age of 16 weeks, rats were instrumented for monitoring of blood pressure and renal function. After intrauterine stress, litter size and birth weight were reduced, whereas hematocrit at birth was increased. Renal blood flow, glomerular filtration rate, and the glomerular filtration fraction were increased significantly after intrauterine stress. High sodium intake did not change renal function and blood pressure in control animals. However, during high sodium intake in intrauterine stress offspring, renal blood flow, glomerular filtration rate, and the filtration fraction were decreased, and blood pressure was increased. In addition, these animals developed severe albuminuria, an important sign of renal dysfunction. Thus, a suboptimal fetal microenvironment, which impairs renal development, results in sodium-dependent hypertension and albuminuria.
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- 2005
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35. Reduced uteroplacental blood flow alters renal arterial reactivity and glomerular properties in the rat offspring.
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Sanders MW, Fazzi GE, Janssen GM, de Leeuw PW, Blanco CE, and De Mey JG
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- Adaptation, Physiological, Adenylyl Cyclases metabolism, Adrenergic Agents pharmacology, Adrenergic Fibers physiology, Albuminuria etiology, Animals, Birth Weight, Colforsin pharmacology, Creatinine blood, Female, Fetal Distress etiology, Hematocrit, Hypertension, Renal etiology, Isoproterenol pharmacology, Kidney Glomerulus embryology, Kidney Glomerulus ultrastructure, Ligation, Litter Size, Male, Nephrectomy, Phenylephrine pharmacology, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Wistar, Receptors, Adrenergic, beta-2 biosynthesis, Receptors, Adrenergic, beta-2 genetics, Renal Artery drug effects, Renal Artery embryology, Serotonin pharmacology, Vasoconstriction drug effects, Fetal Distress physiopathology, Kidney Glomerulus physiopathology, Placenta blood supply, Renal Artery physiopathology, Uterus blood supply
- Abstract
Fetal malnutrition and hypoxia may modify organ system maturation and result in cardiovascular diseases in the adult. We tested whether intrauterine stress (IUS) leads to persistent alterations of renal biology. In rats, intrauterine stress was induced by ligation of the uterine arteries at day 17 of pregnancy. Renal arteries of the 21-day-old male offspring were isolated to study pharmacological reactivity. Kidneys were dissected to analyze renal structure and beta-adrenoceptor expression. At 21 days of age, half of the animals underwent unilateral left nephrectomy. At the age of 12 weeks, rats were instrumented for blood pressure monitoring, blood sampling, and renal function measurements. After IUS, litter size and birth weight were reduced, whereas the hematocrit was increased. Renal arterial responses to beta-adrenergic stimulation and sensitivity to adenylyl cyclase activation were increased, along with the renal expression of beta2-adrenoceptors. At 21 days and at 6 months of age, the number and density of the glomeruli were reduced, whereas their size was increased. The filtration fraction and urinary albumin concentration were increased 12 weeks after intrauterine stress. In control rats, removal of the left kidney at 21 days of age did not affect kidney function and blood pressure. However, after IUS, the remaining right kidney failed to compensate for the loss of the left kidney, and blood pressure was increased. In conclusion, prenatal stress transiently modifies renal arterial reactivity and results in long-lasting adverse effects on renal structure and function and on renal compensatory mechanisms.
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- 2004
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36. Tissue angiotensin-converting enzyme in imposed and physiological flow-related arterial remodeling in mice.
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Hilgers RH, Schiffers PM, Aartsen WM, Fazzi GE, Smits JF, and De Mey JG
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- Alleles, Angiotensin II physiology, Animals, Arteries anatomy & histology, Arteries enzymology, Carotid Arteries pathology, Female, Hyperplasia, Hypertrophy, Ligation, Male, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Peptidyl-Dipeptidase A chemistry, Peptidyl-Dipeptidase A deficiency, Peptidyl-Dipeptidase A genetics, Postpartum Period, Pregnancy, Protein Structure, Tertiary, Sequence Deletion, Stress, Mechanical, Carotid Arteries enzymology, Hemorheology, Membrane Proteins physiology, Peptidyl-Dipeptidase A physiology, Uterus blood supply
- Abstract
Objective: To test whether membrane-bound angiotensin I-converting enzyme (t-ACE) is involved in arterial remodeling, we applied unilateral carotid artery (CA) ligation and studied uterine arteries (UA) before, during, and after pregnancy in t-ACE-/- and t-ACE+/+ mice. RESULTS- In CA of t-ACE-/- mice, blood pressure, outer diameter (D), and medial cross-sectional area (mCSA) were reduced, whereas blood flow (BF) and the number of medial cells (mC) were not modified. In the ligated CA, mCSA and number of mC were increased while outer D and distensibility were reduced. These changes were significantly less pronounced in t-ACE-/- than t-ACE+/+ mice. In UA of t-ACE-/- mice, D was larger and mCSA was unaltered. At term pregnancy, D and mCSA of the UA were reversibly increased. Structural changes of UA during and after pregnancy were comparable in both strains., Conclusions: t-ACE contributes to arterial structure and remodeling. It plays a major role in hyperplastic inward remodeling of the CA imposed by blood flow cessation, but it is not essential for outward hypertrophic and subsequent inward hypotrophic remodeling of the UA during and after pregnancy.
- Published
- 2004
- Full Text
- View/download PDF
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