Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

Abstract

Background: Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation.

Objective: We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate.

Study design: A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025).

Results: We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker (P < .001). A significant correlation (R² = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were intercellular adhesion molecule-1-positive, in none of the 14 placentas with failure of physiologic transformation that were intercellular adhesion molecule-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure (P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation.

Conclusion: Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies.

Keywords: ICAM-1; acute atherosis; endothelial activation; failure of physiologic transformation; placental basal plate; spiral arteries; trophoblast activation.

Figure 1. Different statuses of spiral artery physiologic transformation and ICAM-1 expression

Complete physiologic transformation of spiral arteries: A, presence of endothelium (blue) and trophoblast cells (red) in vessel wall; and D, absence of endothelial intercellular adhesion molecule (ICAM)-1 expression (arrow) with ICAM-1-negative trophoblast cells (blue, arrowhead). Failure of physiologic transformation of spiral arteries: B, characterized by spiral arteries with presence of endothelium (blue, arrowhead) and smooth muscle cells (green, arrow) without arterial invasion of trophoblast cells (red) as seen in artery in center (blue linings on left and lower right of figure corresponding to neighboring veins); and E, presence of endothelial ICAM-1 (red, arrow) with trophoblast cells (blue, arrowhead). Partial physiologic transformation of spiral arteries: C, presence of endothelium (blue), trophoblast cells (red, arrow), and smooth muscle cells (green, arrow) in part of vessel; and F, presence of endothelial ICAM-1 (red, arrow) with trophoblast cells (blue, arrowhead) and smooth muscle cells (green). Note presence of intra-arterial trophoblasts (yellow arrow) in partial physiologic transformation of spiral arteries. Scale represents 50 μm. Original magnification: ×640.

Figure 2. Macrophages and spiral artery physiologic transformation

Complete physiologic transformation of spiral arteries: A and C, few CD68⁺ macrophages (red, arrows) around endovascular trophoblast cells (A, blue) and presence of endothelium (C, blue) in vessels with normal trophoblastic invasion. Failure of physiologic transformation of spiral arteries: B and D, numerous CD68⁺ macrophages (arrows) around vessels, with presence of endothelium (D, blue), absence of intra-arterial trophoblast cells (B, blue), and presence of smooth muscle cells (B and D, green) in spiral arteries. Scale represents 50 μm. Original magnification: ×640.

Figure 3. Histochemical and immunohistochemical characteristics of atherosis

Atherosis lesion recognized with hematoxylin-eosin stain: A, note presence of foam cells (arrows) reactive with oil red O, as shown in D, confirming presence of lipids, which are B, not observed in vessels with normal trophoblastic invasion or C, absence of trophoblastic invasion also reacted with oil red O. Atherosis was observed in spiral arteries using triple-antibody technique that showed arterial smooth muscle cells (E, green), trophoblast cells surrounding but not replacing vessel walls (F, blue), and presence of macrophages in vessel’s intima (G, red, arrow). H, These cell subtypes are clearly shown in combined photograph. Triple-antibody immunohistochemistry for smooth muscle (alpha-actin, E), trophoblasts (cytokeratin, F), macrophages (CD68, G), and their combination (H). Scale represents 50 mm. Original magnification: ×640. A, Hematoxylin-eosin and B to D, oil red O stains.

Figure 4. Summary of immunohistochemical characteristics of spiral artery physiologic transformation in basal plate of different pregnancy conditions studied

Clustered bar chart showing summary of immunohistochemical characteristics of spiral arteries in basal plate of different pregnancy conditions studied. *Data were obtained from n_a = 179 arteries from n_p = 123 placentas; **Failure of physiologic transformation considers complete and partial failure; ¶Placentas intercellular adhesion molecule (ICAM)-1-positive include spiral artery endothelial and/or extravillous trophoblast reactivity; §Atherosis was identified in preterm labor (n_p = 6), preterm premature rupture of membranes (n_p = 9), preeclampsia (n_p = 7), small for gestational age (n_p = 3), fetal death (n_p = 4), and normal pregnancies (n_p = 1). n_a, number of arteries; n_p, number of placentas.