Expression of Biglycan in First Trimester Chorionic Villous Sampling Placental Samples and Altered Function in Telomerase-Immortalized Microvascular Endothelial Cells

Abstract

Objective— Biglycan (BGN) has reduced expression in placentae from pregnancies complicated by fetal growth restriction (FGR). We used first trimester placental samples from pregnancies with later small for gestational age (SGA) infants as a surrogate for FGR. The functional consequences of reduced BGN and the downstream targets of BGN were determined. Furthermore, the expression of targets was validated in primary placental endothelial cells isolated from FGR or control pregnancies. Approach and Results— BGN expression was determined using real-time polymerase chain reaction in placental tissues collected during chorionic villous sampling performed at 10 to 12 weeks’ gestation from pregnancies that had known clinical outcomes, including SGA. Short-interference RNA reduced BGN expression in telomerase-immortalized microvascular endothelial cells, and the effect on proliferation, angiogenesis, and thrombin generation was determined. An angiogenesis array identified downstream targets of BGN, and their expression in control and FGR primary placental endothelial cells was validated using real-time polymerase chain reaction. Reduced BGN expression was observed in SGA placental tissues. BGN reduction decreased network formation of telomerase-immortalized microvascular endothelial cells but did not affect thrombin generation or cellular proliferation. The array identified target genes, which were further validated: angiopoetin 4 ( ANGPT4 ), platelet-derived growth factor receptor α ( PDGFRA ), tumor necrosis factor superfamily member 15 ( TNFSF15 ), angiogenin ( ANG ), serpin family C member 1 ( SERPIN1 ), angiopoietin 2 ( ANGPT2 ), and CXC motif chemokine 12 ( CXCL12 ) in telomerase-immortalized microvascular endothelial cells and primary placental endothelial cells obtained from control and FGR pregnancies. Conclusions— This study reports a temporal relationship between altered placental BGN expression and subsequent development of SGA. Reduction of BGN in vascular endothelial cells leads to disrupted network formation and alterations in the expression of genes involved in angiogenesis. Therefore, differential expression of these may contribute to aberrant angiogenesis in SGA pregnancies.

Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases

“…The placentae of third-trimester idiopathic FGR pregnancies were associated with lower BGN mRNA and protein expression [ 172 ], reconfirmed in first-trimester SGA placental tissues [ 173 ]. It has been proposed that lowered placental BGN levels may contribute to FGR by promoting thrombosis or structural alterations [ 172 ].…”

“…Within the placenta, BGN protein expression was localized to endothelial cells and subendothelial cells of the perivascular region of fetal capillaries [ 172 ]. Interestingly, reduced BGN expression in telomerase-immortalized microvascular endothelial cells did not meaningfully affect apoptosis, proliferation, or thrombin generation [ 173 ]. However, these conditions negatively regulate angiogenic activities, suggesting that BGN is proangiogenic.…”

Unbiased placental secretome characterization identifies candidates for pregnancy complications

“…In the context of GDM, ANGPT2 has been reported be differentially secreted from cultured trophoblast of the term placenta in GDM pregnancy 61 , but no maternal serum analysis was described. Similarly, altered placental expression of ANGPT2 were reported for SGA 62 and one study has found it to serve as a predictive biomarker for IUGR 63 .…”

Inhibition of Stromal Biglycan Promotes Normalization of the Tumor Microenvironment and Enhances Chemotherapeutic Efficacy

“…[42] Targeting ANGPT2 signaling in tumor vasculature can restore vascular stability and decrease tumor growth and metastasis [43]. It has been shown that ANGPT2 is downstream of biglycan signaling in telomerase-immortalized microvascular endothelial cells [44]. Furthermore, BGN was positively associated with ANGPT2 expression in human breast cancers.…”