Preterm premature rupture of membranes: vascular endothelial growth factor and its association with histologic chorioamnionitis.
OBJECTIVE
We hypothesize that vascular endothelial growth factor, a known angiogenic and permeability factor that is locally expressed in fetal membranes and decidua, may be the primary regulator in the pathway that eventually leads to preterm premature rupture of membranes. Our objective was to test the hypothesis that, both in the presence and in the absence of histologic chorioamnionitis, there is an increased expression of the vascular endothelial growth factor gene and its receptor Flt-1 in the human fetal membranes.


METHODS
Membranes were sampled from a region that was distinct as the rupture site from three groups of patients with preterm premature rupture of membranes. Groups 1 and 2 differed only in the length of the latency period from rupture of the membranes to delivery. Group 3 included preterm patients with intact membranes, who acted as control subjects. All patients who were selected for the study lacked clinical signs of chorioamnionitis and were delivered by cesarean delivery. Tissue samples were analyzed for interleukin-6 gene expression by Northern blot analysis and for the presence of interleukin-6 protein by immunocytochemistry. The expression of vascular endothelial growth factor and Flt-1 genes was analyzed by in situ hybridization.


RESULTS
All tissue samples from group 1 and five tissue samples from group 2 (designated as group 2A) showed expression of the interleukin-6 gene and the presence of interleukin-6 protein in the fetal membranes (P <.001) and were therefore identified as inflamed. Five tissue samples from the patients in group 2 (designated as group 2B) and all control tissue samples showed neither evidence of interleukin-6 gene expression nor the presence of its protein and therefore were identified as not inflamed. Vascular endothelial growth factor and Flt-1 gene expression were increased significantly in the fetal membrane and decidua samples that were obtained from the noninflamed tissues from group 2B (P <.005) yet showed further enhancement in expression in the inflamed tissues.


CONCLUSIONS
The expression patterns of vascular endothelial growth factor and Flt-1 genes are indicative of a molecular pathologic condition of fetal membranes, regardless of their inflammatory status, which suggests their role as a primary regulator of preterm premature rupture of membranes.
Daneshmand
Sean S
SS
Division of Perinatal Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla 92093-0802, USA.
Chmait
Ramen H
RH
Moore
Thomas R
TR
Bogic
Ljubica
L
D000293:Adolescent; D000328:Adult; D002821:Chorioamnionitis / Q000378:metabolism* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005321:Extraembryonic Membranes / Q000378:metabolism; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040281:Vascular Endothelial Growth Factor Receptor-1