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GATA1-mediated macrophage polarization via TrkB/cGMP-PKG signaling pathway to promote the development of preeclampsia
Wushan Li1,2, Fei Hou2, Di Cheng2
1Department of Obstetrics and Gynecology, Cheeloo College of Medicine, Shandong University, Ji'nan City, Shandong Province, China.
Insights
Reducing GATA1 levels in preeclampsia (PE) promotes M2 macrophage polarization via the TrkB/cGMP-PKG pathway, improving PE symptoms. This highlights GATA1 as a potential therapeutic target for PE.
Area of Science:
- Reproductive biology
- Immunology
- Molecular signaling
Background:
- Preeclampsia (PE) is a severe pregnancy complication impacting maternal and fetal health, lacking definitive treatments.
- The transcription factor GATA1 and the NTRK2/cGMP-PKG pathway are implicated in PE pathogenesis, but mechanisms are unclear.
- Macrophages at the maternal-fetal interface play a key role, with their function regulated by the cGMP-PKG pathway.
Purpose of the Study:
- To investigate the role of GATA1 in preeclampsia pathogenesis.
- To elucidate how GATA1 regulates the TrkB/cGMP-PKG signaling pathway in macrophages.
- To determine the contribution of GATA1-mediated dysregulation to preeclampsia development.
Main Methods:
- Utilized cell lines (THP-1, HTR-8/Svneo), human umbilical vein endothelial cells (HPVECs), and Sprague-Dawley rats.
- Employed gene knockdown and overexpression techniques to study GATA1 and TrkB effects.
- Conducted transcriptomic sequencing, bioinformatics analysis, animal experiments, and clinical sample analysis.
Main Results:
- GATA1 knockdown mitigated PE symptoms, an effect reversed by TrkB overexpression.
- Knockdown of GATA1 increased M2 macrophage polarization and significantly decreased TrkB, cGMP, and PKG expression.
- GATA1 knockdown promoted trophoblast cell migration and blood vessel formation, while NTRK2 overexpression inhibited these effects.
Conclusions:
- GATA1 knockdown modulates macrophage M2 polarization through the TrkB/cGMP-PKG pathway, impacting PE progression.
- Significant associations between GATA1 and the TrkB/cGMP-PKG pathway were found in transcriptomic data from PE placentas.
- GATA1 and its downstream signaling represent a potential therapeutic target for preeclampsia.
Background:
Preeclampsia (PE) is a severe pregnancy complication characterized by hypertension and proteinuria. PE poses a substantial threat to the health of both mothers and fetuses, and currently, there is no definitive treatment available. Recent studies have indicated that the transcription factor GATA1 may be implicated in the pathological processes of PE, but the underlying mechanism remains elusive. NTRK2/cGMP-PKG signaling pathway plays a crucial role in regulating the function and polarization of macrophages, which are key immune cells at the maternal-fetal interface. This study aims to investigate the role of GATA1 in the pathogenesis of PE, with a specific focus on how GATA1-regulated TrkB/cGMP-PKG signaling in macrophages and its dysregulation contribute to the development of preeclampsia.
Methods:
By employing THP-1 cells, co-culture systems of THP-1 cells and HTR-8/Svneo, HPVECs and Sprague-Dawley (SD) rats, in conjunction with gene knockdown and overexpression techniques, we explored the effects of GATA1 on the TrkB/cGMP-PKG signaling pathway. Transcriptomic sequencing, bioinformatics analysis, animal experiments, and clinical sample collection were conducted to validate the role of GATA1 in PE.
Results:
Knockdown of GATA1 mitigated the symptoms of PE, and this effect was reversed by overexpression of TrkB. In comparison with the control group, the proportion of M2 cells elevated significantly in the sh-GATA1 group (P < 0.001). In addition, the protein expressions levels of TrkB, cGMP, and PKG were significantly decreased in the sh-GATA1 group were significantly decreased compared with those in the control group (P < 0.001, P < 0.001, P < 0.001, P < 0.05, respectively). Moreover, knockdown of GATA1 significantly promoted the migration rate and blood vessel formation of HTR-8/Svneo cells (P < 0.001, P < 0.05, respectively) which inhibited by overexpression of NTRK2 (P < 0.05, P < 0.01, respectively).
Conclusions:
The study demonstrated that knockdown of GATA1 modulates M2 polarization of macrophage through the TrkB/cGMP-PKG signaling pathway, influencing the progression of PE. In addition, significant associations between GATA1 and the TrkB/cGMP-PKG signaling pathway were identified in the transcriptomic data from PE patient placentas.
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