Regulation of Uterine Spiral Artery Remodeling: a Review

Abstract

Extravillous trophoblast remodeling of the uterine spiral arteries is essential for promoting blood flow to the placenta and fetal development, but little is known about the regulation of this process. A defect in spiral artery remodeling underpins adverse conditions of human pregnancy, notably early-onset preeclampsia and fetal growth restriction, which result in maternal and fetal morbidity and mortality. Many in vitro studies have been conducted to determine the ability of growth and other factors to stimulate trophoblast cells to migrate across a synthetic membrane. Clinical studies have investigated whether the maternal levels of various factors are altered during abnormal human pregnancy. Animal models have been established to assess the ability of various factors to recapitulate the pathophysiological symptoms of preeclampsia. This review analyzes the results of the in vitro, clinical, and animal studies and describes a nonhuman primate experimental paradigm of defective uterine artery remodeling to study the regulation of vessel remodeling.

Keywords: Animal models; Preeclampsia; Uterine artery remodeling.

Fig. 1

The two-stage placental model of preeclampsia in which it has been proposed [111] that impaired remodeling of uterine spiral arteries (“poor placentation”) is the pathway to stage 1 preeclampsia (placental dysfunction) and the preclinical stage before development of the maternal clinical syndrome (stage 2). Reprinted from Staff [20]

Fig. 2

Hypothetical scheme depicting how abnormal trophoblast invasion and spiral artery remodeling result in placental ischemia, endothelial dysfunction, and hypertension in preeclampsia. Reprinted from Palei et al. [17]

Fig. 3

(a) sFlt-1 levels in uterine vein and (b) VEGF protein quantified by proximity ligation assay (signals/nuclear area × 10⁴) in the anchoring villi on day 60 in untreated and estradiol (E₂)-treated baboons. *P < 0.05

Fig. 4

Percent remodeling of uterine spiral arteries (i.e., number of vessels exhibiting trophoblast invasion divided by total number of vessels counted) on day 60 of gestation in baboons untreated, treated with estradiol (E₂), or treated with E₂ plus VEGF DNA. *Different (P < 0.01) from values in other two groups