Evidence for Immune Cell Involvement in Decidual Spiral Arteriole Remodeling in Early Human Pregnancy

Abstract

Decidual artery remodeling is essential for a healthy pregnancy. This process involves loss of vascular smooth muscle cells and endothelium, which are replaced by endovascular trophoblasts (vEVTs) embedded in fibrinoid. Remodeling is impaired during preeclampsia, a disease of pregnancy that results in maternal and fetal mortality and morbidity. Early vascular changes occur in the absence of vEVTs, suggesting that another cell type is involved; evidence from animal models indicates that decidual leukocytes play a role. We hypothesized that leukocytes participate in remodeling through the triggering of apoptosis or extracellular matrix degradation. Decidua basalis samples (8 to 12 weeks gestation) were examined by immunohistochemistry to elucidate associations between leukocytes, vEVTs, and key remodeling events. Trophoblast-independent and -dependent phases of remodeling were identified. Based on a combination of morphological attributes, vessel profiles were classified into a putative temporal series of four stages. In early stages of remodeling, vascular smooth muscle cells showed dramatic disruption and disorganization before vEVT presence. Leukocytes (identified as uterine natural killer cells and macrophages) were apparent infiltrating vascular smooth muscle cells layers and were matrix metalloproteinase-7 and -9 immunopositive. A proportion of vascular smooth muscle cells and endothelial cells were terminal deoxynucleotidyl transferase dUTP nick-end labeling positive, suggesting remodeling involves apoptosis. We thus confirm that vascular remodeling occurs in distinct trophoblast-independent and -dependent stages and provide the first evidence of decidual leukocyte involvement in trophoblastindependent stages.

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

“…In species with hemochorial placentation, such as humans, uterine vascular changes include increased permeability, angiogenesis and structural remodeling of most spiral arteries (SA) to reduce vasoactivity and increase capacity. 1,2 In humans, inadequate modification of decidual and myometrial SA is often accompanied by preeclampsia (PE) and/or intrauterine growth restriction (IUGR). 3,4 SA remodeling is progressive and involves loss of vascular smooth muscle coat and elastic lamina, mural invasion by trophoblast cells that deposit nonvasoactive fibrinoid and transient replacement of vascular endothelial cells by intravascular trophoblast.…”

“…3,4 SA remodeling is progressive and involves loss of vascular smooth muscle coat and elastic lamina, mural invasion by trophoblast cells that deposit nonvasoactive fibrinoid and transient replacement of vascular endothelial cells by intravascular trophoblast. 2,5 In humans, SA remodeling normally occurs during first and second trimester with ~2/3 of these vessels dilating 5-10 fold. SA remodeling slows maternal blood flow, minimizes turbulence and optimizes exchange time with the fetal circulation.…”

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Abstract OBJECTIVE-Our goal was to define mechanisms that protect murine pregnancies deficient in spiral arterial (SA) remodeling from hypertension, hypoxia and intra-uterine growth restriction.STUDY DESIGN-Micro-ultrasound analyses were conducted on virgin, gestation day (gd) 2,4,7,9,10,12,14,16,18 and postpartum BALB/c (WT) mice and BALB/c-Rag2 −/− /Il2rg −/− mice, an immunodeficient strain lacking SA remodeling.

RESULTS-Rag2−/− /Il2rg −/− dams had normal SA flow velocities, greatly elevated uterine artery flow velocities between gd10-16 and smaller areas of placental flow from gd14 to term than controls. Maternal heart weight and output increased transiently.

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“…STUDY DESIGN-Micro-ultrasound analyses were conducted on virgin, gestation day (gd) 2,4,7,9,10,12,14,16,18 and postpartum BALB/c (WT) mice and BALB/c-Rag2 −/− /Il2rg −/− mice, an immunodeficient strain lacking SA remodeling.…”

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion

“…Matrix metalloproteinase 12 or macrophage elastase is also expressed by both the endometrium and trophoblast. Major sources of MMP12 are uterine natural killer cells and macrophages [43], interstitial and endovascular trophoblasts, as well as vascular smooth muscle cells [44]. The MMP12 is a key mediator of elastolysis and contributes to the remodeling of spiral arteries.…”