Clinical Study On The Expression Of MMP-2 In Maternal Blood Andumbilical Blood Of Preeclampsia Pregnancies

Hypertensive disorder complicating pregnancy is a specificcomplication to pregnancy, characterized by hypertension and proteinuriawith women during their gestational age. The basic pathological change isgeneralized spasm of arteriolae.It may worsen to be preeclampsia(PE),eveneclampsia.The disorder is one of the leading cause of maternal and fetalmorbidity and mortality.The etiology is still unknown.Researches show thatthe abnormal expression of matrix metalloproteinases(MMPs) correlates withthe occurrence of the hypertensive disorder complicating pregnancy.Toevaluate the relativity between the serum levels of MMP-2 and theoccurrence and severity of PE ,we collected maternal and umbilical bloodfrom normotensive and preeclamptic pregnant women in the third trimester.Objective:Through investigating the expression of MMP-2 andpro-MMP-2 of materal and umbilical blood from normotensive andpreeclamptic pregnant women at term,we study the relationship betweenMMP-2 and the pathogenesis of hypertensive disorder complicatingpregnancy.It may help us to determine the etiology and to defend and treatthe disease.Method:14 normotensive and 38 preeclamptic pregnant women,15 ofwhom were mild PE and 23 of whom were severe PE,were selected from thepregnant women who delivered in the Second Hospital of JiLin Universityfrom Oct.2004 to Dec.2005.None of them gave a history of PE complicatedwith chronic hypertension , pregnancy with chronic hypertension andautoimmunological disease or received blood transfusion and immunologicaltreatment.The maternal and umbilical blood was collected beforedelivery.The serum levels of MMP-2 and pro-MMP-2 were detected bySDS-PAGE zymography. Photographs of the gel were scanned by an imagingdensitometer and quantified using the NIH image157 Software program.Result:1,There was expression of MMP-2 and pro-MMP-2 in thenormotensive and preeclamptic maternal serum.The MMP-2 of the severe PEincreased to 179.5%±63.6%(P<0.05)of control . The MMP-2 of the mildPE increased to 127.0%±89.6%(P>0.05)of control .The former differencewas significant,but the latter was not. The MMP-2 of the severe PE increasedto 141.3 % ( P>0.05 ) of that of mild PE.The difference was notsignificant.There was not statistical significance on the comparison ofpro-MMP-2 among the terms.2,There was expression of MMP-2 and pro-MMP-2 in thenormotensive and preeclamptic umbilical serum. There was not statisticalsignificance on the comparison of proMMP-2 among the terms(P>0.05).3,The neonatal weight negatively correlated with the levels ofthe maternal serum MMP-2,and have no correlation with the umbilical serumMMP-2.Discussion: In this study,the levels of MMP-2 in maternal serum of PEgroup were significantly higher than that of control group.The levels ofpro-MMP-2 also appeared upward trend.However,it was found by Qiao et al.thatthe expression of MMP-2mRNA in preeclamptic placentae in the third trimesterappeared a descent tendency.Thus,it suggests that the main resource of MMP-2in maternal blood of preeclamptic pregnancies is not the placenta,but thevascular endothelium.We also found that the levels of MMP-2 and pro-MMP-2in umbilical serum had few change,which might affected by the decreasedexpression by placenta.The certain cause needs more studies.So we believe thatMMP-2 has less correlation with reduced invasive capacity of trophoblast in PEduring the third trimester.Myers et al. found that in the plasma of pregnancies who subsequentlydeveloped PE and normal pregnancies ,MMP-2 levels were significantlyelevated at 22 weeks and at diagnosis in the PE group,but there was nodifference at 26 weeks.They also found that TIMP-1 levels were significantlyreduced in the PE group at 26 weeks.So an imbalance in the MMP-2/TIMP-1was found in patients who subsequently developed PE.All these suggest that theincreased MMP-2 activity may contribute to the endothelial dysfunction that iscentral to the pathophysiology of PE. We found that the maternal serum levels ofMMP-2 of the PE group was significantly higher than that of the controlgroup.Moreover,the levels of MMP-2 appeared positive correlation with theseverity of PE.Thus,the levels of MMP-2 of the maternal serum may have thecapacity to clue us on the severity of PE.The study also implicates that there is afactor(s) in the preeclamptic pregnancies in the third trimester which canpromote the expression of MMP-2.The factor(s) directly correlates with thedevelopment of PE. It is consistent with the study result of Narumiya et al..Thetalso found that vascular endothelial growth factor (VEGF) could stimulateMMP-2 release of the human umbilical vein endothelial cells (HUVECs) fromhealthy pregnancies.Hunter et al. determined by radioimmunoassay that theserum VEGF concentrations of the predelivery and at the 30 weeks wereelevated in the preeclampsia group than in the normotensive group,whichsuggested that VEGF was likely to be one of the factors promoting MMP-2 inpreeclampsia serum.The elevated levels of VEGF in blood is a compensatorymechanism which promote the self-repairing of impaired vascularendothelium.But in the pathological state of PE,the elevation of VEGF can notpromote self-repairing,moreover,can aggravate the constricted state of impairedvessel.Bosio et al.believed that MMPs from endothelial cells induced by VEGFcould promote the lysis of ET and make the vessels contrict.Several researchersfound that preeclampsia levels of ET were two or three times of that ofnormotensive pregnancies.After giving ectogenous ET continuously,thepregnant ewe appeared the hemodynamic state like PE.Thus VEGF ofpreeclamptic patients make the vessels contrict by MMPs and ET,and increasethe peripheral resistance. VEGF contains a hydrophobic secretory signalsequence,which increases microvascular endothelial cell prostacyclinproduction.It promotes endothelial expression of procoagulant activity.Merchant et al. incubated the HUVECs from preeclamptic pregnancies andnormal pregnancies for 12 hr in standard culture conditions. Preeclampticendothelial cells demonstrate significantly enhanced MMP-2, TIMP-1 andTIMP-2 release compared to normal cells.They found that the HUVECs fromnormal pregnancies release more MMP-2 under hypoxia conditions thanstandard conditions,which implied that the release of MMP-2 from endothelialcells was significantly affected by the oxygen tension of the surroundings.Inhypertensive disorder complicating pregnancy,the ischemia and anoxic causedby generalized spasm of arteriolae may aggravate the impairing of vascularendothelium. Whether it is the direct reason promoting the release of MMP-2required more studies.We also found that the levels of MMP-2 in maternal serum had effect onthe neonatal outcome.Since the quantity of specimens is small,its effect onneonatal outcome requires more study.Serum MMP-2 and other veneous factorsaggravate the impairing of vascular endothelium,bring imbalance ofvasoconstrictor and vasodilator,aggravate the generalized spasm ofarteriolae,reduce the function and refusion of all the systems and organs anddecline of the refusion of placenta.All these cause deficiency of maternal-fetalsupplying of blood,which cause fetal growth retardation,even death.Conclusion:1,The maternal serum levels of MMP-2 of the preeclampsiapregnancies are elevated signicantly compared with that of the normotensivepregnancies.The levels rise with the severity of PE.It may affect the outcomeof the newborns. In the third trimester of preeclamptic pregnancies,MMP-2have little correlation with the decline of invasive capacity oftrophoblast.However,the increased levels of MMP-2 in preeclamptic maternalserum may correlate with the dysfunction of vascular endothelium,which isone of the main pathogenesis of PE.2,The umbilical serum levels of MMP-2 is unlikely tocorrelate with the severity of PE.3,The maternal and umbilical serum levels of proMMP-2 isunlikely to correlate with the development of PE.4,MMPs are one of the main cause of the hypertensivedisorder complicating pregnancy by some mechanism.5,MMP-2 is a good molecular sign of the hypertensivedisorder complicating pregnancy ,and it may be an biochemical index for theseverity of PE and the outcome of the newborns.