ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts

Abstract

Proper placental development and function is crucial for a healthy pregnancy, and there has been substantial research to identify markers of placental dysfunction for the early detection of pregnancy complications. Low first-trimester levels of a disintegrin and metalloproteinase 12 (ADAM12) and pregnancy-associated plasma protein-A (PAPP-A) have been consistently associated with the subsequent development of preeclampsia and fetal growth restriction. These molecules are both metalloproteinases secreted by the placenta that cleave insulin-like growth factor binding proteins (IGFBPs), although ADAM12 also has numerous other substrates. Recent work has identified ADAM12, and particularly its shorter variant, ADAM12S, as a regulator of the migration and invasion of trophoblasts into the lining of the uterus, a critical step in normal placental development. While the mechanisms underlying this regulation are not yet clear, they may involve the liberation of heparin-binding EGF-like growth factor (HB-EGF) and/or IGFs from IGFBPs. In contrast, there has been relatively little functional work examining PAPP-A or the IGFBP substrates of ADAM12 and PAPP-A. Understanding the functions of these markers and the mechanisms underlying their association with disease could improve screening strategies and enable the development of new therapeutic interventions.

Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

“…ADAM12 SNPs and their potential roles in PA risk through trophoblast regulation is particularly intriguing because trophoblastic invasion is thought to lead to vascular malformations and PA [49]. ADAM12 is also associated with other risk factors of PA such as preeclampsia that have shared etiology and pathophysiology with PA including trophoblast invasion [3, 47]. In addition, ADAM12 is primarily expressed in the placenta [35], highlighting the potential clinical significance of our findings.…”

“…This GWAS meta-analysis identified 10 SNPs in ADAM12 (ADAM metallopeptidase domain 12), a highly expressed gene in the placenta and implicated in cellular function and maintenance. ADAM12 regulates the migration and invasion of trophoblasts into the lining of the uterus, a critical step in normal placental development [47] [48]. The two ADAM12 SNPs, rs7094759 and rs12264492 among our top GWAS meta-analysis hits mapped to trophoblast-like cell chromatin interaction in functional analyses.…”

FLT1 and transcriptome-wide polyadenylation site (PAS) analysis in preeclampsia

“…In both EO-PE and LO-PE, the isoform encoding membrane-bound SDC1 was preferentially upregulated. Likewise, ADAM12 expresses two alternate PAS mRNA isoforms, ADAM12-S and ADAM12-L, encoding short (S,secreted) and long (L,membrane-bound) forms of metalloproteinase-disintegrin 12 61 , 62 (Fig. 5d ).…”

Pregnancy‐associated plasma protein‐A is positively correlated with first‐trimester skin microvascular reactivity

“…First‐trimester maternal PAPP‐A levels are positively related to birth weight, and this marker is used routinely in first‐trimester screening, as low PAPP‐A levels are associated with both chromosomal anomalies and adverse pregnancy outcomes, such as small‐for‐gestational age, preterm labor, pre‐eclampsia and stillbirth. PAPP‐A is also detectable in non‐pregnant individuals and is elevated in patients with acute coronary syndrome, but the exact mechanistic function of PAPP‐A in non‐pregnant individuals or during pregnancy remains unclear.…”