Using the Reduced Uterine Perfusion Pressure model of preeclampsia to study the blood brain barrier permeability
DOI:
https://doi.org/10.15448/1980-6108.2018.2.29631Keywords:
animal models, blood-brain barrier, preeclampsia, eclampsia, toxemia of pregnancy, hypertension, posterior leukoencephalopathy syndrome, pregnancy complications.Abstract
AIMS: To use the Reduced Uterine Perfusion Pressure (RUPP) model for preeclampsia to describe and evaluate the blood brain barrier permeability in pregnant rats.
METHODS: Forty-one pregnant Wistar rats were divided into different intervention groups between 13 to 15 days of gestation: Pregnant-Control (PC; n=12), Reduced Uterine Perfusion Pressure (RUPP; n=15), Invasive Blood Pressure-Control (IBP; n=7) and Reduced Uterine Perfusion Pressure and Invasive Blood Pressure (RUPP-IBP; n=7). The 14 rats of groups IBP and RUPP-IBP had their mean arterial pressure measured at day 21. All animals were then sacrificed, administered Evans Blue dye through the tail vein and perfused with paraformaldehyde 4%. Brains were removed and evaluated by a blinded pathologist. Results are presented as means and standard errors. Comparisons between the groups were performed using Student's t-test for continuous variables and Fisher’s exact test for categorical variables. Statistical significance was set as a p value less than 0.05.
RESULTS: Mean arterial pressure averaged 85.4±2.2 mmHg in the IPB group and 102.5±8.3 mmHg in the RUPP-IPB group (p=0.002). Among all the RUPP rats (RUPP and RUPP-IBP groups), 82% had a positive staining with Evans Blue dye for at least one of the brain hemispheres, while none of the pregnant control rats (PC and IBP groups) had brain staining (p<0.001).
CONCLUSIONS: In this study, altered permeability of the blood brain barrier was successfully reproduced in pregnant rats exposed to the RUPP protocol. Therefore, we concluded that the RUPP model is a valid surrogate to study blood brain barrier abnormalities.
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References
NHBPEPWG. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183(1):S1-S22. https://doi.org/10.1067/mob.2000.107928
Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013;170(1):1-7. https://doi.org/10.1016/j.ejogrb.2013.05.005
Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF, Bennett WA, Granger JP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension. 2001;37(4):1191. https://doi.org/10.1161/01.HYP.37.4.1191
Spradley FT, Tan AY, Joo WS, Daniels G, Kussie P, Karumanchi SA, Granger JP. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension. Hypertension. 2016;67(4):740-7. https://doi.org/10.1161/HYPERTENSIONAHA.115.06783
Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension. 2006;48(4):711-6. https://doi.org/10.1161/01.HYP.0000238442.33463.94
Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel J, Souza JP. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG. 2014;121 Suppl 1:14-24. https://doi.org/10.1111/1471-0528.12629
Brewer J, Owens MY, Wallace K, Reeves AA, Morris R, Khan M, LaMarca B, Martin JN Jr. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol. 2013;208(6):468.e1-6. https://doi.org/10.1016/j.ajog.2013.02.015
Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494-500. https://doi.org/10.1056/NEJM199602223340803
Karumanchi SA, Lindheimer MD. Advances in the understanding of eclampsia. Curr Hypertens Rep. 2008;10(4):305-12. https://doi.org/10.1007/s11906-008-0057-3
Porcello Marrone LC, Gadonski G, de Oliveira Laguna G, Poli-de-Figueiredo CE, Pinheiro da Costa BE, Lopes MFT, Brunelli JFP, Diogo LP, Huf Marrone AC, Da Costa JC. Blood-brain barrier breakdown in reduced uterine perfusion pressure: a possible model of posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis. 2014;23(8):2075-9. https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.03.012
Nienartowicz A, Link S, Moll W. Adaptation of the uterine arcade in rats to pregnancy. J Dev Physiol. 1989;12(2):101-8.
Cardoso LM, Pedrosa ML, Silva ME, Moraes MF, Colombari E, Chianca DA. Baroreflex function in conscious rats submitted to iron overload. Braz J Med Biol Res. 2005;38(2):205-14. https://doi.org/10.1590/S0100-879X2005000200008
Gage GJ, Kipke DR, Shain W. Whole animal perfusion fixation for rodents. J Vis Exp. 2012;(65). pii: 3564. https://doi.org/10.3791/3564
Li J, LaMarca B, Reckelhoff JF. A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. Am J Physiol Heart Circ Physiol. 2012;303(1):H1-8. https://doi.org/10.1152/ajpheart.00117.2012
McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animal models of preeclampsia; uses and limitations. Placenta. 2011;32(6):413-9. https://doi.org/10.1016/j.placenta.2011.03.010
Brennan L, Morton JS, Quon A, Davidge ST. Postpartum Vascular Dysfunction in the Reduced Uteroplacental Perfusion Model of Preeclampsia. PLoS One. 2016;11(9):e0162487. http://doi.org/10.1371/journal.pone.0162487
Cornelius DC, Amaral LM, Wallace K, Campbell N, Thomas AJ, Scott J. Reduced uterine perfusion pressure T-helper 17 cells cause pathophysiology associated with preeclampsia during pregnancy. Am J Physiol Regul Integr Comp Physiol. 2016; 311(6):R1192-R1199. https://doi.org/10.1152/ajpregu.00117.2016
Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia. Hypertension. 2007;50(1):14-24. https://doi.org/10.1161/HYPERTENSIONAHA.106.079442
Auer LM. The pathogenesis of hypertensive encephalopathy. Experimental data and their clinical relevance with special reference to neurosurgical patients. Acta Neurochir Suppl (Wien). 1978;27:1-111.
Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ. Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension. 2010;56(5):1003-8. https://doi.org/10.1161/HYPERTENSIONAHA.110.158931
