ABSTRACT
Objectives: Aberrations in placental vascular development compromising fetal supply of oxygen and essential nutrients can be a significant contributor to intrauterine growth restriction (IUGR). The development of placental vascular tree is under the influence of two families of growth factors, namely the vascular endothelial growth factor (VEGF) family and angiopoietin/TEK family. In this study, we have examined the expression of angiogenesis-related growth factors, mainly VEGF family and angiopoietin-TEK (endothelial-specific receptor tyrosine kinase) family genes in placentae from IUGR pregnancies uncomplicated by preeclampsia (PE) compared to normal pregnancies.Methods: Placentae from normotensive IUGR (n = 42) and appropriate for gestational age (AGA) pregnancies (n = 47) were collected and examined histologically. Clinical parameters were obtained from the medical records. Real-time quantitative PCR was performed to assess placental transcript abundance of VEGF, PGF, FLT1, ANGPT1, ANGPT2, and TEK normalized to a panel of reference genes. Associations of placental transcript abundance of the genes with maternal, placental, and neonatal parameters were tested.Results: Placental transcript abundance for VEGF (relative expression 10.81 versus 12.98, p < .001), PGF (12.14 versus 13.8, p < .001) and ANGPT2 (3.67 versus 9.55, p = .002) were significantly lower in IUGR placentae compared to AGA. The transcript level of VEGF showed significant negative correlation with birth weight (r = -0.419, p = .006), placental weight (r = -0.318, p = .040), placental length (r = -0.389, p = .011) and breadth (r = -0.308, p = .047) only in the IUGR group. Presence of histopathological features of hypoxia correlated with significantly higher transcript levels of PGF in IUGR placentae (12.6 versus 10.9, p = .046).Conclusion: The low levels of VEGF transcripts may be responsible for the impaired angiogenesis in IUGR placentae. The significance of higher relative expression of PGF in the presence of chronic hypoxia needs to be explored.
ABSTRACT
BACKGROUND: Structural or functional defects in the placenta, are the primary cause of growth restriction of the fetus. Morphological examination of such placentas from intrauterine growth restricted (IUGR) fetuses often appears deceptively normal. Evaluation of angiogenesis and fetoplacental vasculature is critical to understand the underlying pathogenesis of fetal growth restriction in both idiopathic as well as cases where it is thought to be secondary to complications like preeclampsia (PE). We analyzed the immaturity of fetoplacental vasculature using CD15, which is a stage specific embryonic antigen known to be expressed in immature endothelium. MATERIAL AND METHODS: One hundred and twelve placentas (81 from IUGR and 31 from gestationally appropriate samples (appropriate for gestational age (AGA)) were collected based on stringent inclusion criteria, and subjected to detailed examination of morphology and microscopy along with immunostaining for CD15. IUGR placentas known to have villous immaturity such as those associated with gestational diabetes, Rh negative pregnancies and anemia were excluded. The time of clinical onset of IUGR, associated complications like PE and oligohydramnios along with clinical variables were recorded. CD15 expression was scored in both distal and proximal vasculature and the values in IUGR and AGA pregnancies were compared and correlated with clinical variables. RESULTS: The mean CD 15 scores in both proximal vasculature (PV) as well as distal (DV) vasculature were significantly higher in the IUGR group compared to AGA (17.7 versus 5.16 in PV and 50.8 versus 23.7 in distal vasculature (DV)). Gestational age had no influence on CD15 staining in PV or DV in IUGR group, whereas preterm AGAs expressed higher CD15 only in the distal vessels. PE, oligohydramnios and the time of onset of IUGR did not influence the fetal vascular immaturity, as measured by CD15 scores. Although none of the clinical or obstetric factors influenced CD15 staining in AGA, fetal vessel immaturity in the IUGR group remained high even after adjusting for confounding variables like maternal age, gestational age and birth weight. Histological features suggestive of chronic hypoxia were significantly higher in IUGR placentas, compared to AGA and correlated positively with CD15 expression. CONCLUSION: Fetoplacental endothelium in both PV and DV is immature in IUGR irrespective of the gestational age or any other associated factors and CD15 immunodetection is a valuable marker for assessment of immaturity.
