Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: A mechanism for the intersection of coagulation and inflammation

Erez, Offer; Romero, Roberto; Kim, Sung Su; Kim, Jung Sun; Kim, Yeon Mee; Wildman, Derek E.; Than, Nándor Gábor; Mazaki‐Tovi, Shali; Gotsch, Francesca; Pineles, Beth L.; Kusanovic, Juan Pedro; Espinoza, Jimmy; Mittal, Pooja; Mazor, Moshe; Hassan, Sonia S.; Kim, Chong Jai

doi:10.1080/14767050802034859

Cited by 43 publications

(25 citation statements)

References 144 publications

(171 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…55 Activating proteases include thrombin, trypsin, factor Xa, factor XIIa/X, 56 and MMP-1. 33 Although overexpression of PAR-1 in the preeclamptic placenta has been previously demonstrated, 35 we show herein, for the first time to our knowledge, that PAR-1 expression is increased in the vasculature of women with preeclampsia. Because PAR-1 is mostly confined to the endothelium in healthy human arteries, whereas during an inflammatory process, its expression is enhanced in regions associated with leukocyte influx, 57 it is logical to infer that the increase in vascular PAR-1 during preeclampsia is mediated by infiltrating neutrophils.…”

Section: Discussionmentioning

confidence: 42%

“…18 Matrix metalloproteinase-1 is known to activate PAR-1, 33 which plays critical roles in coagulation, inflammation, and vascular homeostasis 34 ; and its expression is increased in preeclamptic compared with healthy placentas. 35 We hypothesized that neutrophils infiltrated into the vasculature of women with preeclampsia promote VSMC expression of PAR-1. Thus, we evaluated the potential of neutrophils, TNF-␣, and ROS to induce expression of PAR-1 in vitro.…”

Section: Vascular Par-1 Is Increased In Preeclampsiamentioning

confidence: 99%

See 1 more Smart Citation

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Estrada-Gutiérrez

Cappello

Mishra

et al. 2011

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

This study was conducted to determine the following: (1) whether matrix metalloproteinase-1 (MMP-1) is increased in systemic vessels of preeclamptic women, (2) whether this increase might be mediated by neutrophils, and (3) whether MMP-1 could be responsible for vascular dysfunction. Omental arteries and plasma were collected from healthy pregnant and preeclamptic women. Omental arteries were evaluated for gene and protein expression of MMP-1, collagen type 1␣, tissue inhibitor of metalloproteinase-1, and vascular reactivity to MMP-1. Gene and protein expression levels were also evaluated in human vascular smooth muscle cells (VSMCs) co-cultured with activated neutrophils, reactive oxygen species, or tumor necrosis factor ␣. Vessel expression of MMP-1 and circulating MMP-1 levels were increased in preeclamptic women, whereas vascular expression of collagen or tissue inhibitor of metalloproteinase-1 were down-regulated or unchanged. In cultured VSMCs, the imbalance in collagen-regulating genes of preeclamptic vessels was reproduced by treatment with neutrophils, tumor necrosis factor ␣, or reactive oxygen species. Chemotaxis studies with cultured cells revealed that MMP-1 promoted recruitment of neutrophils via vascular smooth muscle release of interleukin-8. Furthermore, MMP-1 induced vasoconstriction via protease-activated receptor-1, whose expression was significantly increased in omental arteries of preeclamptic women and in VSMCs co-cultured with neutrophils. Collectively, these findings disclose a novel role for MMP-1 as a mediator of vasoconstriction and vascular dysfunction in preeclampsia.

show abstract

Section: Discussionmentioning

confidence: 42%

Section: Vascular Par-1 Is Increased In Preeclampsiamentioning

confidence: 99%

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Estrada-Gutiérrez

Cappello

Mishra

et al. 2011

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Endothelial cells also secrete sFlt-1, and this secretion is induced by the activation of PAR-2, a receptor that is activated by blood coagulation serine proteinases (37). In this context, it is of interest to note that PAR-1, a receptor for thrombin, is more highly expressed in preeclamptic placenta than in normal pregnancy (38). Therefore, together with our findings, we speculate that thrombin, generated in the placenta, activates PAR-1 and acts as an enhancer of sFlt-1 expression in trophoblasts and consequently promotes preeclampsia.…”

Section: Discussionmentioning

confidence: 98%

Thrombin enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts; possible involvement in the pathogenesis of preeclampsia

Zhao

Koga

Osuga

et al. 2012

Fertility and Sterility

View full text Add to dashboard Cite

“…Each of these pathways is central in the deployment of an inflammatory response: cytokine-cytokine receptor interaction, Jak-STAT signaling, the complement and coagulation pathway, NOD-like receptor signaling, systemic lupus erythematosus (specifically the complement C1q complex), and chemokine signaling. Interestingly, components of these pathways have been previously linked to both normal parturition [57, 75, 76, 159, 180, 201, 213, 221, 226–228, 235, 271, 274, 308] and the “Great Obstetrical Syndromes” [32, 33, 64, 79–82, 84, 85, 89, 238, 267, 291, 295, 307, 320], including preterm labor [28, 58, 74, 77, 83, 86–88, 119, 120, 164, 165, 211, 223, 246, 252, 254, 290, 292, 293, 316–319]. Indeed, our group has reported an association between activation of the NALP3 inflammasome and the common pathway of parturition [119].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term

Mittal¹,

Romero²,

Tarca³

et al. 2010

Journal of Perinatal Medicine

Self Cite

141

113

View full text Add to dashboard Cite

Aims: To characterize the transcriptome of human myometrium during spontaneous labor at term. Methods: Myometrium was obtained from women with (ns19) and without labor (ns20). Illumina ᭨ HumanHT-12 microarrays were utilized. Moderated t-tests and false discovery rate adjustment of P-values were applied. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for a select set of differentially expressed genes in a separate set of samples. Enzyme-linked immunosorbent assay and Western blot were utilized to confirm differential protein production in a third sample set. Results: 1) Four hundred and seventy-one genes were differentially expressed; 2) gene ontology analysis indicated enrichment of 103 biological processes and 18 molecular functions including: a) inflammatory response; b) cytokine activity; and c) chemokine activity; 3) systems biology pathway analysis using signaling pathway impact analysis indicated six significant pathways: a) cytokine-cytokine receptor interaction; b) Jak-STAT signaling; and c) complement and coagulation cascades; d) NOD-like receptor signaling pathway; e) systemic lupus erythematosus; and f) chemokine signaling pathway; 4) qRT-PCR confirmed over-expression of prostaglandin-endoperoxide synthase-2, heparin binding epidermal growth factor (EGF)-like growth factor, chemokine C-C motif ligand 2 (CCL2/MCP1), leukocyte immunoglobulin-like receptor, subfamily A member 5, interleukin (IL)-8, IL-6, chemokine C-X-C motif ligand 6 (CXCL6/GCP2), nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta, suppressor of cytokine signaling 3 (SOCS3) and decreased expression of FK506 binding-protein 5 and aldehyde dehydrogenase in labor; 5) IL-6, CXCL6, CCL2 and SOCS3 protein expression was significantly higher in the term labor group compared to the term not in labor group. Conclusions: Myometrium of women in spontaneous labor at term is characterized by a stereotypic gene expression pattern consistent with over-expression of the inflammatory response and leukocyte chemotaxis. Differential gene expression identified with microarray was confirmed with qRT-PCR using an independent set of samples. This study represents an unbiased description of the biological processes involved in spontaneous labor at term based on transcriptomics.

show abstract

Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: A mechanism for the intersection of coagulation and inflammation

Cited by 43 publications

References 144 publications

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

Thrombin enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts; possible involvement in the pathogenesis of preeclampsia

Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term

Contact Info

Product

Resources

About