Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Abstract

Objective To assess and compare circulating tissue inhibitor of metalloproteinase 3 (TIMP‐3) concentrations between women with pre‐eclampsia and healthy pregnant women. We also aimed to determine the relationships between circulating TIMP‐3 and matrix metalloproteinase 2 (MMP‐2), MMP‐9, TIMP‐1, and TIMP‐2 concentrations in pre‐eclampsia. Methods A primary case–control study included patients with pre‐eclampsia (n = 219) and gestational hypertension (n = 118), healthy pregnant women (n = 214), and non‐pregnant women (n = 66), and a replication case–control study included patients with pre‐eclampsia (n = 177) and healthy pregnant women (n = 124), all from southeastern Brazil. Plasma TIMP‐3, MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2 concentrations were assessed using commercially available enzyme‐linked immunosorbent assay kits, and the relationships between them were analyzed using Spearman's correlation. Results In our primary study, patients with pre‐eclampsia and gestational hypertension exhibited increased TIMP‐3 concentrations compared with healthy pregnant women (both P < 0.0001) and non‐pregnant women (both P < 0.001). These findings were confirmed in the replication study, showing elevated TIMP‐3 concentrations in women with pre‐eclampsia versus healthy pregnant women (P < 0.001). We found no difference in TIMP‐3 concentrations between early‐onset and late‐onset pre‐eclampsia. Moreover, TIMP‐3 concentrations were significantly correlated with plasma concentrations of TIMP‐1 (r = 0.2333; P = 0.0086) and MMP‐2 (r = 0.2159; P = 0.0156) in pre‐eclampsia. Conclusions Circulating TIMP‐3 concentration is increased in women with pre‐eclampsia compared with healthy pregnant women, and it is positively correlated with plasma MMP‐2 and TIMP‐1 concentrations in pre‐eclampsia.

Antihypertensive therapy responsiveness and adverse outcomes in preeclampsia: insights into molecular mechanisms underlying cardiovascular and renal complications

“…However, we identified a higher number of significant differentially methylated probes located on the TIMP-3 promoter, as well as an increased TIMP-3 expression in corresponding placental samples from early-onset PE compared to controls, which denotes DNA methylation of TIMP-3 promoter as an epigenetic mechanism in PE (Cruz et al, 2022). Recently, we found that circulating TIMP-3 is increased in patients with PE compared with healthy pregnancy, and these TIMP-3 levels were positively correlated with MMP-2 and TIMP-1 concentrations in PE (Palei et al, 2022). These findings may contribute to understand the relevance of TIMP-3 in the pathophysiology of PE.…”

Type I interferon alters invasive extravillous trophoblast function

“…We found heightened expression of several genes associated with increased PE risk including TNFSF13B, TFPI2, TIMP3, RBM25, IGF2R and CSF1 21,[23][24][25][26] in IFN-EVTs compared with control EVTs (Figure 3e). We also observed increased expression of complement activation components that have specifically been implicated in PE pathogenesis (CFH, CFB, C1R, C1S) in IFN-exposed EVTs 27,28 .…”

Understanding the Role of Chemerin in the Pathophysiology of Pre-Eclampsia

“…The regulation of angiogenesis in PE has been extensively studied over recent years, leading to the identification of novel angiogenesis-related PE biomarkers, such as tissue inhibitor of metalloproteinase 3 (TIMP-3) [ 104 ]. As mentioned before, chemerin serum levels are elevated in pre-eclamptic patients.…”