Late-Onset Preeclampsia Is Linked to Extensive Remodeling of the Placental Extracellular Matrix

Background: Late-onset preeclampsia (LO-PE) is the most prevalent clinical phenotype of preeclampsia and, although traditionally considered less strongly associated with placental dysfunction than early-onset disease, increasing evidence supports the presence of relevant placental alterations. The extracellular matrix (ECM) is a key regulator of villous architecture, tissue mechanics, trophoblast behavior, vascular remodeling, and angiogenesis. This study aimed to characterize ECM remodeling in placentas from women with LO-PE. Patients and Methods: A prospective observational study was conducted in 111 pregnant women, including 68 with LO-PE and 43 healthy controls. Placental samples were collected immediately after delivery. Gene expression of elastogenesis-related markers, cross-linking enzymes, fibrillar collagens, matrix-remodeling regulators, and endothelial–matrix signaling molecules was assessed by RT-qPCR. Protein expression was evaluated by immunohistochemistry. Differences between groups were analyzed using non-parametric tests with Benjamini–Hochberg correction, and correlations among ECM markers were explored using Spearman analysis. Results: LO-PE placentas showed significantly increased expression of tropoelastin (TE), fibulin-4 (FBLN-4), fibulin-5 (FBLN-5), fibrillin-1 (FBN-1), lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL-1), collagen type I (COL-I), collagen type III (COL-III), and matrix metalloproteinase-2 (MMP-2) at both gene and protein levels. Conversely, gene and protein expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) and epidermal growth factor-like domain 7 (EGFL7) showed a marked decrease in the placentas of pregnant women with LO-PE. These findings indicate enhanced elastogenesis, increased matrix cross-linking, greater fibrillar collagen deposition, and an imbalance in matrix turnover. Correlation analysis further suggested that, although the FBLN-4/FBLN-5 axis remained preserved, LO-PE placentas displayed partial disruption of the broader ECM transcriptional network. Conclusions: LO-PE placentas exhibit a coordinated but dysregulated ECM remodeling phenotype involving elastic, collagenous, proteolytic, and endothelial–matrix regulatory pathways. These alterations support ECM remodeling as a relevant biological feature of LO-PE placental pathophysiology.