Immaturity for gestational age of microvasculature and placental barrier in term placentas with high weight.

OBJECTIVE: Villous immaturity for gestational age is a multifactorial developmental deviation associated with unexpected placental insufficiency, fetal hypoxia and term fetal death. In our previous work we have shown that immature CD15+/CD31+/CD34+ endothelial cells were an important indicator of placental villous immaturity and chronic insufficiency. The aim of this study was to perform a comparative analysis of CD15-marked immaturity in the vessel walls between normal and pathological term placentas of clinically and structurally heterogenous groups with normal, low and high weight. STUDY DESIGN: 165 clinically normal and pathological placentas of gestational age 39-42 with normal weight (25-75 percentile), low weight (<10 percentile) and high weight (>90 percentile) were structurally and immunohistochemically analyzed. Excluded were placentas with a severe form of placental insufficiency associated with intrauterine fetal death, low APGAR-score, genetic and chromosomal diseases or placental inflammations. The distribution patterns of CD15, CD31 and CD34 were assessed separately in the macrovasculature, microvasculature and placental barrier (PB) - associated capillaries. RESULTS: All placental groups with normal weight, low weight and high weight include normal, accelerated villous maturation or villous immaturity independent of their weight. However, a significant increase of immature CD15+/CD31+/CD34+ endothelial cells was detected in microvasculature and PB -associated capillaries in high weight-placentas (63.5%/52.2%), compared to those of normal weight (13.8%/8.2%) and low weight (16.1%/17.8%). The distribution of macrovascular immature CD15+/CD31+/CD34+ endothelial cells did not show such marked differences. CONCLUSION: We have identified the immaturity of microvasculature and PB -associated capillaries with a pathological persistency of immature CD15+/CD31+/CD34+ endothelial cells and a reduction of terminally differentiated CD15-/CD31+/CD34+ endothelial cells in a structurally and clinically heterogeneous group of high weight-placentas. We assume that immaturity of placental vessels are part of prenatal adaptational processes that can be recruited in different emergency situations and may provide potential targets of therapeutic correction of placental growth and chronic insufficiency. We therefore recommend the use of CD15-based immunophenotyping as a method to identify latent unfavorable conditions of fetal development in the intrauterine life and individual risk of disease in the postnatal period.

The embryo-placental CD15-positive "vasculogenic zones" as a source of propranolol-sensitive pediatric vascular tumors.

OBJECTIVE: Propranolol-induced involution is a unique biological feature of some pediatric vascular tumors, for instance infantile hemangioma (IH), cerebral cavernoma or chorioangioma. Currently, the cellular origin of these distinct tumors is unclear. In this study, we tested the hypothesis that propranolol-responsive vascular tumors are derived from common vessel-forming CD15 + progenitor cells which occur in early gestation. The aim of this study was to identify the tumor-relevant CD15 + progenitors at the early stages of embryo-placental development. MATERIALS AND METHODS: Human embryo-placental units of 4-8 weeks gestation and pediatric vascular tumors were tested for expression of the tumor-relevant markers CD15, CD31 and CD34. RESULTS: Placental vessel-forming progenitors were characterized by immunostaining for CD15, CD31, and CD34. In embryonic tissue, a discontinuous CD15+/CD31+/CD34 + progenitors was detected in immature vessels of the skin, neural tube, spinal and cerebral meninges. Similarly, vessels in IH and chorioangioma exhibited a co-expression of CD15, CD31, and CD34. In contrast, the majority of embryonic vessels presented a CD31+/CD34+, but CD15-negative immunophenotypic pattern. DISCUSSION: Our results suggest the existence of a CD15+ "vasculogenic zones" in the embryo-placental unit as well as in IH and chorioangioma. A site-specific correlation between normal embryo-placental and tumoral vessel-forming CD15 + progenitors was demonstrated. CONCLUSION: Hence, site- and stage-specific CD15 + progenitors of vascular wall could be considered as propronalol-sensitive targets and source of pre- and postnatal vascular tumors. We propose, that the CD15+ "vasculogenic zones" are a site-specific reserve of multi-lineage progenitors that could be recruited in pre- and postnatal emergency situations.

CD15 - a new marker of pathological villous immaturity of the term placenta.

INTRODUCTION: Idiopathic immaturity is one of the main reasons for latent placental insufficiency and antenatal hypoxia. Postnatal identification of the immature placental phenotype may help early stratification of a heterogeneous population of newborns and individually identify risk of disease in the immediate postnatal life. The aim of the study was to determine the relevant diagnostic markers associated with pathological placental immaturity. METHODS: 111 tissue samples from normal and pathological term placentas with persisting villous immaturity comprised the comparative immunohistochemical study (CD15, CD34). Positive immunohistochemical reactions were quantitatively assessed in the chorionic plate and vessels of the villi of different histological type. RESULTS: We have shown that pathological villous immaturity is attended by significantly increased CD15-expression in the macro- and microvascular endothelium compared with the normal placenta. CD34-expression was not different from that in normal placentas. DISCUSSION: This paper documents the correlation of CD15+ endothelium in the macrovascular fetoplacental vessels with a severe form of villous immaturity associated with fetal hypoxia/asphyxia and erythroblastosis. Increased CD15-expression only in the microvascular segment of the fetoplacental vessels correlated with moderate villous immaturity and was associated with GDM, idiopathic fetal macrosomia and nonspecific chronic villitis. CONCLUSION: We propose that "immature" CD15+ endothelium is an important diagnostic marker of persisting villous immaturity and chronic placental dysfunction. The level of CD15 expression in the macro- and microvasculature reflects the degree of pathological placental villous immaturity.

Transient CD15-positive endothelial phenotype in the human placenta correlates with physiological and pathological fetoplacental immaturity.

OBJECTIVE: Placental growth and villous maturation are critical parameters of placental function at the end of pregnancy. A failure in these processes leads to the development of placental dysfunction, as well as fetal and neonatal mortality and morbidity. The aim of the study was to determine the relevant diagnostic markers associated with pathological placental development. STUDY DESIGN: Forty tissue samples from normal placentas of different gestational age and 68 pathological term placentas with defective villous maturation (GDM, idiopathic IUFD, preeclamsia, HELLP syndrome) comprised the comparative immunohistochemical study (CD15, CD45 and CD34). Positive immunohistochemical reactions were quantitatively assessed in the chorionic plate and vessels of the villi of different histological type. RESULTS: Physiologically immature placentas of the first and second trimester and pathologically immature term placentas were characterized by marked endothelial CD15-immunostaining. A significant loss of CD15-positive endothelium of the placentas was associated with a physiological and accelerated villous maturity. A spatio-temporal correlation was shown for CD15+ endothelial cells (ECs) and the number of CD45+ stromal cells (SCs). A negative temporal correlation was shown for CD15+ ECs and CD15+ myelomonocytes in the fetal blood. CD34 expression in the ECs was stable during the pregnancy. CONCLUSION: A correlation between a transient CD15-positive endothelial phenotype and a physiological and pathological fetoplacental immaturity was demonstrated. Physiological and accelerated placental maturation was accompanied by a significant disappearance of CD15-positive endothelium. We propose that "immature" CD15+ endothelium is an important diagnostic marker of the physiological and pathological fetoplacental immaturity.

Imbalance of expression of bFGF and PK1 is associated with defective maturation and antenatal placental insufficiency.

OBJECTIVE: Defective placental maturation is associated with restricted functional capacity and adverse perinatal fetal outcomes. The aim of the study was a comparative analysis of the role of mRNA expression of various angiogenic factors in placental maturation defects. STUDY DESIGN: We examined the mRNA expression patterns of prokineticin 1 (PK1), its receptors (PKRs), basic-fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in tissue from third-trimester placentae that exhibited delayed or accelerated villous maturation. RESULTS: The expression of PK1 and PKR2 was elevated in placental tissue exhibiting accelerated maturation and a predominant differentiation of terminal villi. The opposite was found in tissue exhibiting delayed maturation and deficiency of the terminal villi. In addition, low expression of bFGF correlated with the predominant differentiation of terminal villi, whereas the opposite was observed when terminal villi were deficient. The expression of VEGF, PIGF, and PKR1 showed no significant differences between the groups. CONCLUSION: Defective placental maturation is associated with an imbalance of expression of bFGF and PK1. Our results demonstrate an involvement of the PK1/PKR2-signalling pathway in the regulation of the functional adequate capillarization in late pregnancy. We propose the bFGF/PK1-ratio as a monitor of placental function and a possible indicator of latent clinical problems, such as placental dysfunction leading to fetal hypoxia.