1. This meta-analysis reviewed animal studies on functional vascular adaptation during pregnancy, focusing on vasodilator and vasoconstrictor responses in mesenteric arteries. 2. The analysis found uniformly upregulated flow-mediated vasodilation across species but heterogeneity in responses to pharmacological agents. 3. While most studies examined late pregnancy, the quality of evidence was limited due to a lack of randomization and blinding in the underlying studies. 4. Systematic reviews of animal data can provide new insights, identify gaps, and increase the efficacy of animal research compared to individual studies.

1. Functional adaptation during pregnancy: a meta-analysis
of animal studies
J. van Drongelen

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. During pregnancy
Human Weeks of gestation
Rat NP 5 11 16 21 Days of gestation
Chamberlain and Broughton (1998); Slangen et al. (1996); Danielson et al. (1995)

4. Vasodilation
Mesenteric vascular bed important!

5. Local vascular tone
ECM

6. Local vascular tone
ECM

7. Local vascular tone
ECM
Pressure

8. Local vascular tone
ECM
Pressure

9. Measuring vasomotion
Response
SMC
EC

10. Measuring vasomotion
Effect
Emax
50%
Stimulus
EC50%

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. Goal
Selection of studies concerning
• Healthy subjects in their first pregnancy
• Healthy nulliparous subjects
• Comparable age
• Vasodilator and vasoconstrictor mesenteric responses

13. Pubmed and Embase search
Three components
1. Pregnancy
2. Mesenteric arteries
3. Vasodilator and vasoconstrictor responses

14. Component Description
Pregnancy "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] OR
vasodilator 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. 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. 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. 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. Meta-analysis
x3

19. Results

 
=
= =

ECM
Pressure


20. In summary
SDR WR Mice Guinea pigs
Vasodilation
- flow-mediated vasodilation   . .
- compliance  = . .
- vasodilator agents (EC)  =  
- vasodilator agents (SMC)  . . .
Vasoconstriction
- myogenic reactivity ? = . .
- vasoconstrictor agents (SMC)  =  =

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. 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. Take home message
Systematic review of animal studies
There is no excuse

24. Acknowledgements
Dr. CR Hooijmans
Dr. RBM de Vries
Drs. L. ten Bos
Prof. Dr. PABM Smits
Prof. Dr. FK Lotgering
Prof. Dr. MJ Ritskens
Prof. Dr. MEA Spaanderman