D2-40/podoplanin expression in the human placenta☆
Introduction
During pregnancy, maternal uterine blood vessels undergo dramatic vascular remodeling to accommodate the increased utero-placental blood flow, which supports growth and development of the placenta and the fetus. Adequate utero-placental blood flow is essential for normal placental perfusion and critical to fetal health, survival and successful pregnancy. Recent work indicates that like uterine blood vessels, dramatic changes in the uterine lymphatic vessel system also take place in the vascular remodeling process during pregnancy [1], [2].
In general, the lymphatic vasculature acts for a parallel collection circuit to blood vessels in most tissues and organs, possibly even the brain [3], actively regulating fluid balance, lipid transport and immune cell trafficking. Lymphatics are the main route for collection of filtered interstitial fluid and cells in tissues. Although the lymphatic system plays an important role in vessel remodeling and fluid homeostasis in the uterus during pregnancy, no lymphatic vessels have been reported in the placenta and interstitial fluid homeostasis in the placenta remains enigmatic. Recently, a study by our group did show that many lymphatic-associated markers are expressed in the placenta including VEGF-C, VEGF-D, and VEGFR-3/Flt-4 [4]. Lymphatic vascular hyaluronan receptor LYVE-1 is expressed in trophoblasts, which appears to compensate for the absence of CD44 in the placenta [4].
D2-40 is a recently developed monoclonal antibody raised against an M2A antigen [5], [6], a Mr 40,000 surface sialoglycoprotein associated with germ cell neoplasia and fetal testicular gonocytes. In tumor pathology, D2-40 has been used to detect lymphatic invasion in tumor tissues. D2-40 specifically recognizes human podoplanin, and has been demonstrated as a selective marker for lymphatic endothelium. To determine if D2-40/podoplanin is expressed in the human placenta, immunoreactivity of D2-40/podoplanin was examined in the 1st, 2nd, and 3rd trimester placentas. VEGFR-3, the main lymphatic endothelial growth factor receptor, and CD31, a marker for blood vessel endothelium, were also examined. There was a unique pattern of D2-40 expression in villous stroma in the human placenta. D2-40/podoplanin was expressed in the human placenta throughout pregnancy and its expression was significantly reduced in placentas from preeclamptic pregnancies. This suggests that D2-40/podoplanin is developmentally expressed in the normally human placenta, and that alterations in D2-40 expression during preeclampsia may underlie interstitial imbalances seen in this pregnancy disorder.
Section snippets
Tissue sample collection
The third trimester placentas from normotensive and preeclamptic pregnancies were collected from the main hospital, Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S). First and second trimester placentas were collected from selective pregnancy terminations at the Department of Obstetrics and Gynecology, the First Hospital of Harbin Medical University, China. Placenta collection was approved from both Institutions. Normal pregnancy is defined as maternal blood pressure
D2-40/podoplanin expression in villous stroma
To determine if D2-40/podoplanin is expressed in the human placenta, we first examined immunoreactivities of D2-40, CD31, and VEGFR-3 by immunostaining of serial tissue sections of placentas from normotensive pregnancies (n = 3). CD31 was used as a blood vessel endothelial marker and VEGFR-3 was used as a lymphatic vessel endothelial marker. Very interestingly, a strong D2-40 expression was detected in the villous stroma (Fig. 1A), in the area of sub-syncytiotrophoblasts towards stroma (Fig. 1
Discussion
D2-40 is a monoclonal antibody directed against human podoplanin, a transmembrane mucoprotein that is expressed in lymphatic endothelial cells. D2-40 reacts with an O-linked sialoglycoprotein (MW 40 K) found on lymphatic endothelium, but does not react with blood vessel endothelium [8]. Thus, D2-40 has been used as lymphatic endothelial marker to study lymph-angiogenesis in physiological and pathological tissue samples and has been proved to be helpful in determining lymphatic invasion in tumor
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This study was supported in part by grants from National Institute of Health, NICHD (HD36822) and NHLBI (HL65997).