Robert Pijnenborg

A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre‐eclamptic pregnancies

Objective To investigate trophoblast invasion and vascular changes in placental bed spiral arteries in normal and severe pre‐eclamptic pregnancies.

Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy

Trophoblastic invasion of the human decidua has been studied in 48 intact uteri with pregnancies ranging from 8 to 18 weeks after the last menstrual period. Some cytotrophoblast invades the distal segments of the spiral arteries to become endovascular while the rest diffusely infiltrates the decidua as an interstitial invader. The interstitial cytotrophoblast reaches the myometrium and gives rise to the characteristic placental bed giant cells. As the placental site enlarges the lateral spiral arteries come to lie obliquely; new openings into the intervillous space are created but this readjustment of the placental blood supply may cause focal superficial decidual necrosis. The physiological changes converting the spiral to the uteroplacental arteries are effected in the upper decidua by the action of endovascular and perivascular cytotrophoblast, whereas in the deeper decidua endovascular trophoblast is principally involved. Endometrial granulocytes aggregate in the region of maternal tissue degeneration with the heaviest trophoblast invasion but the role played by these cells in placentation is unknown.

Placental bed spiral arteries in the hypertensive disorders of pregnancy

Objective— The investigation of the histology of the placental bed spiral arteries in normal pregnancy and in pregnancies complicated by hypertension, with or without proteinura.

THE “GREAT OBSTETRICAL SYNDROMES” ARE ASSOCIATED WITH DISORDERS OF DEEP PLACENTATION

Defective deep placentation has been associated with a spectrum of complications of pregnancy including preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. The disease of the placental vascular bed that underpins these complications is commonly investigated with targeted biopsies. In this review, we critically evaluate the biopsy technique to summarize the salient types of defective deep placentation, and propose criteria for the classification of defective deep placentation into 3 types based on the degree of restriction of remodeling and the presence of obstructive lesions in the myometrial segment of the spiral arteries.

Review article: Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals

Trophoblast invasion is an essential component of haemochorial placentation and has to be considered to relation to reactive changes in the maternal uterine tissues. Some comparative aspects of human and laboratory rodents are discussed and, although there is an obvious phylogenetic gap between the two, many characteristics of placental development are found to be analogous. Trophoblast growth into the uterus is different in different species: localized trophoblast growth forming a bulky tissue (mouse, rat, hamster) contrast with a dispersion of independent trophoblastic elements, forming an interstitial invasion (guinea pig, man). In the rat, mouse, hamster and man retrograde intra-arterial trophoblast migration occurs in maternal vessels supplying blood to the developing placenta. Early changes in maternal tissue might influence trophoblast behaviour. Decidualization probably is a key phenomenon, and the relation of decidual necrosis to trophoblast invasion is considered. Some kind of controlled immune response by the mother also may be involved. These considerations apply to stromal or interstitial invasion as well as to intravascular trophoblast migration but, for the latter, haemodynamic factors probably influence tissue reactions.

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

We used rats transgenic for the human angiotensinogen (hAogen) gene and the human renin (hRen) gene and crossed the strains to produce a model of preeclampsia in the dams. The female (n=9) hAogen × male hRen cross had severe (telemetry-measured) hypertension and albuminuria, which developed during the last trimester of pregnancy and subsided after delivery. The converse cross (n=9) and control (n=9) SD rats did not. We demonstrated that the female hAogen × male hRen cross had agonistic antibodies capable of activating the angiotensin (Ang) II AT1 receptor (AT1R-AA) and defined the epitope on the receptor’s second extracellular loop. The phenomenon also occurs in humans with preeclampsia. The rats displayed renal histology reminiscent of preeclampsia, including fibrin deposition confined to the glomeruli. The complement system was activated in glomeruli and IgG deposits were present that may represent AT1R-AA. Finally, we observed an atherosis-like lesion in the spiral arteries of the placental bed, which we called placental-bed arteriolosclerosis. Our model may be relevant to preeclampsia in humans.

Quantitative analysis of trophoblast invasion in preeclampsia

Background.  The process of physiological conversion of spiral arteries is dependent on the invasion of the interstitium and spiral arteries of the uterine wall by invasive extravillous trophoblast thereby creating a high flow–low resistance vessel. Quantitative data on restriction of trophoblast invasion and failure of spiral artery transformation are limited in preeclampsia.

The Placental Bed

Objectives: To review critically published data concerning fetalmdash;maternal interaction at the placental bed level in normal and complicated pregnancies. Emphasis is placed on the adaptive changes of the uteroplacental vasculature of the placental bed.Methods: Histopathological and immunohistochemical data form the basis of this review. The relevance of recent studies on cultured trophoblast is considered in the light of histological findings.Results: The findings of recent experimental studies on invasive processes and trophoblastmdash;extracellular matrix interaction relate mainly to interstitial trophoblast, since no in vitro model is available for the study of vascular changes. The endovascular pathway of vascular invasion is emphasized, and mechanisms of arterial wall destruction need to be reconsidered since vascular disorganization and disruption may precede trophoblast invasion. There is a need for blood flow studies in relation to histopathological findings. Currently the role of various cytok...

Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats.

Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-&agr; and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia-inducible factor 1&agr; was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an “autoimmune-activating receptor” that could contribute to Ang II sensitivity and possible to preeclampsia.

A role for menstruation in preconditioning the uterus for successful pregnancy

Menstruation is widely viewed as serving no purpose other than to reinitiate the endometrial cycle in the absence of pregnancy. Yet, it is striking that cyclic endometrial decidualization followed by menstrual shedding is confined to the few species, including human beings, where placenta formation entails deep trophoblast invasion of maternal tissues and its vasculature. Both menstruation and pregnancy are inflammatory conditions that cause a degree of physiological ischemia-reperfusion tissue injury, albeit much more so in pregnancy. Thus, the emergence of cyclic menstruation may not have been an evolutionary coincidence but serves to protect uterine tissues from the profound hyperinflammation and oxidative stress associated with deep placentation, a process known as preconditioning. The concept of menstrual preconditioning provides a novel paradigm for understanding how reproductive disorders impact on pregnancy outcome. For example, endometriosis could be viewed as a disorder of exaggerated menstrual preconditioning that confers protection against placentation-related disorders, such as preeclampsia.