Functional adaptation during pregnancy: a meta-analysis                    of animal studiesJ. van Drongelen
Insight in:    1. Cellular pathways involved in pregnancy-induced       vasodilation    2. Systematic overview of literatu...
During pregnancyHuman                                                      Weeks of gestationRat     NP     5        11   ...
Vasodilation  Mesenteric vascular bed important!
Local vascular tone                      ECM
Local vascular tone                      ECM
Local vascular tone                      ECM   Pressure
Local vascular tone                      ECM   Pressure
Measuring vasomotion                         ResponseSMC EC
Measuring vasomotion         Effect  Emax          50%                               Stimulus                       EC50%
Summary    •   Pregnancy induces vasodilation    •   Two types of stimuli (pharmacological / mechanical)    •   G-protein ...
Goal  Selection of studies concerning  • Healthy subjects in their first pregnancy  • Healthy nulliparous subjects  • Comp...
Pubmed and Embase search  Three components  1. Pregnancy  2. Mesenteric arteries  3. Vasodilator and vasoconstrictor respo...
Component               DescriptionPregnancy               "pregnancy"[MeSH Terms] OR "pregnancy"[tiab] OR "pregnancies"[t...
Inclusion and exclusion         Identified studies (n=398)                               Title and abstract               ...
Study characteristics   Species (55 studies)   •   Rodents:        - rat            (n=46)                        SDR    ...
Quality   Randomization     4%   Blinding          0%   Pharmacological stimuli   • EC50%            52%   • Emax         ...
Meta-analysis                x3
Results                                                                       =                                = =     ...
In summary                                 SDR   WR   Mice   Guinea pigsVasodilation- flow-mediated vasodilation         ...
Conclusion  1.   Most studies concern late pregnancy  2.   Quality is limited  3.   Flow-mediated vasodilation is uniforml...
Take home message  Systematic reviews of animal studies  • Give new insight  • Identify lacunas in knowledge  • Lead to ne...
Take home message Systematic review of animal studies           There is no excuse
Acknowledgements      Dr. CR Hooijmans      Dr. RBM de Vries       Drs. L. ten Bos   Prof. Dr. PABM Smits   Prof. Dr. FK L...
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SYRCLE_Drongelen mini symposium sr animal studies 30082012

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SYRCLE_Drongelen mini symposium sr animal studies 30082012

  1. 1. Functional adaptation during pregnancy: a meta-analysis of animal studiesJ. van Drongelen
  2. 2. Insight in: 1. Cellular pathways involved in pregnancy-induced vasodilation 2. Systematic overview of literature (mesenteric arteries) 3. Advantages of systematic review of animal studies
  3. 3. During pregnancyHuman Weeks of gestationRat NP 5 11 16 21 Days of gestation Chamberlain and Broughton (1998); Slangen et al. (1996); Danielson et al. (1995)
  4. 4. Vasodilation Mesenteric vascular bed important!
  5. 5. Local vascular tone ECM
  6. 6. Local vascular tone ECM
  7. 7. Local vascular tone ECM Pressure
  8. 8. Local vascular tone ECM Pressure
  9. 9. Measuring vasomotion ResponseSMC EC
  10. 10. Measuring vasomotion Effect Emax 50% Stimulus EC50%
  11. 11. Summary • Pregnancy induces vasodilation • Two types of stimuli (pharmacological / mechanical) • G-protein coupled receptors are important • Theories mainly based on rats  Mesenteric system is important  Conflicting results in literature Idea • Systematic review  Effect of first pregnancy on vascular responses in mesenteric arteries
  12. 12. Goal Selection of studies concerning • Healthy subjects in their first pregnancy • Healthy nulliparous subjects • Comparable age • Vasodilator and vasoconstrictor mesenteric responses
  13. 13. Pubmed and Embase search Three components 1. Pregnancy 2. Mesenteric arteries 3. Vasodilator and vasoconstrictor responses
  14. 14. Component DescriptionPregnancy "pregnancy"[MeSH Terms] OR "pregnancy"[tiab] OR "pregnancies"[tiab] OR "gestation"[tiab] OR "pregnant"[tiab] OR "maternal-fetal relations"[tiab]Mesenteric arteries "mesenteric arteries"[MeSH Terms] OR "Mesentery/blood supply"[Mesh] OR "mesenteric"[tiab] OR "mesentery artery"[tiab] OR "mesentery arteries"[tiab] OR "mesenterial artery"[tiab] OR "mesenterial arteries"[tiab] OR "arteria mesenterica"[tiab] OR "omental microvessels"[tiab] OR "omental arteries"[tiab] OR "omental artery"[tiab]Vasoconstrictor and "vasoconstriction"[MeSH Terms] OR "vasoconstriction"[tiab] ORvasodilator responses "vasoconstrictions"[tiab] OR "vasoconstrictor agents"[MeSH Terms] OR "vasoconstrictor agents"[Pharmacological Action] OR "vascular resistance"[MeSH Terms] OR "vascular resistance"[tiab] OR "vascular capacitance"[MeSH Terms] OR ("vascular"[tiab] AND "capacitance"[tiab]) OR "vasoconstrictor"[tiab] OR "vasoconstrictors"[tiab] OR "vasopressor"[tiab] OR "vasoactive agonist"[tiab] OR "vasoactive agonists"[tiab] OR "vasopressors"[tiab] OR "vasomotor system"[MeSH Terms] OR "vasomotor system"[tiab] OR "peripheral resistance"[tiab] OR "artery constriction"[tiab] OR "vessel constriction"[tiab] OR "vasoconstrictive"[tiab] OR "vasoconstricting"[tiab] OR "vasoconstricted"[tiab] OR "vasodilation"[MeSH Terms] OR "vasodilation"[tiab] OR "vasodilatation"[tiab] OR "vasodilatating"[tiab] OR "vasodilating"[tiab] OR "vasodilative"[tiab] OR "vasodilatative"[tiab] OR "artery dilation"[tiab] OR "vessel dilation"[tiab] OR "artery dilatation"[tiab] OR "vessel dilatation"[tiab] OR "vasodilator agents"[MeSH Terms] OR "vasodilator agents"[Pharmacological Action] OR "vasodilator"[tiab] OR "vasodilators"[tiab] OR "vasorelaxation"[tiab] OR "Vascular Endothelium Dependent Relaxation"[tiab] OR "Endothelium Dependent Relaxation"[tiab] OR "Vascular Endothelium-Dependent Relaxation"[tiab] OR "Endothelium-Dependent-Relaxation"[tiab] OR "hemodynamics"[MeSH Terms] OR "hemodynamics"[tiab]OR "hemodynamic"[tiab] OR "vasodilated"[tiab] OR "vasoactive agent"[tiab] OR "vasoactive drug"[tiab] OR "vasoactive drugs"[tiab] OR "dilation"[tiab] OR "dilatation"[tiab] OR "contraction"[tiab] OR "relaxation"[tiab]
  15. 15. Inclusion and exclusion Identified studies (n=398) Title and abstract (n=302) - No healthy first pregnancy versus virgin control (n=258) - No mesenteric artery vasoconstrictor/vasodilator response (n=19) - No standard medium (n=5) - No original data; review (n=20) Subtracted studies (n=96) Full article (n=43) - No healthy first pregnancy versus virgin control (n=12) - No mesenteric artery vasoconstrictor/vasodilator response (n=26) - No age-matching (n=5) Included studies (n=55) Responses (r=78) - Response <5 measurements (r=38) - Other blockade than NO, PGI2, endothelium (r=40) Included responses (r=188) - Pharmacological / Electrical (r=160) * EC50 described (r=83) * Emax described (r=63) * Graph present (r=130) - Mechanical (r=28) * Graph present (r=27)
  16. 16. Study characteristics Species (55 studies) • Rodents: - rat (n=46)  SDR (n=27)  WR (n=15)  unknown (n=1) - mouse (n=5) - guinea pig (n=2) • Rabbit (n=1) • Pigs (n=1) Gestational period (188 responses) • Early (r=3) • Mid (r=23) • Late (r=161) • Unknown (r=1)
  17. 17. Quality Randomization 4% Blinding 0% Pharmacological stimuli • EC50% 52% • Emax 39% • Graph 81% • Clear number 74% Mechanical stimuli • Effect size 7% • Graph 96% • Clear number 92%
  18. 18. Meta-analysis x3
  19. 19. Results    = = =  ECM Pressure 
  20. 20. In summary SDR WR Mice Guinea pigsVasodilation- flow-mediated vasodilation   . .- compliance  = . .- vasodilator agents (EC)  =  - vasodilator agents (SMC)  . . .Vasoconstriction- myogenic reactivity ? = . .- vasoconstrictor agents (SMC)  =  =
  21. 21. Conclusion 1. Most studies concern late pregnancy 2. Quality is limited 3. Flow-mediated vasodilation is uniformly upregulated 4. Heterogeneity amongst species 5. Importance of systematic reviews for animal data 6. Difficulty in extrapolation to vasodilator pathways involved in human pregnancy
  22. 22. Take home message Systematic reviews of animal studies • Give new insight • Identify lacunas in knowledge • Lead to new original research • Increase efficancy of animal use • Reduce unnecessary use of animals
  23. 23. Take home message Systematic review of animal studies There is no excuse
  24. 24. Acknowledgements Dr. CR Hooijmans Dr. RBM de Vries Drs. L. ten Bos Prof. Dr. PABM Smits Prof. Dr. FK Lotgering Prof. Dr. MJ RitskensProf. Dr. MEA Spaanderman

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