Journal of ethnopharmacology · 2025
Bushen Tiaojing Decoction promotes endometrial angiogenesis to improve endometrial receptivity by regulating KLF4-mediated mitochondrial function and transcription activity.
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Cao Can, Li Jiena, Zhang Yu, Wu Shixing, Liu Qi, Xi Yu, Chen Can, He Ming
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine has numerous advantages in the treatment of infertility. The traditional Chinese herbal formula Bushen Tiaojing Decoction (BSTJD) is widely used for treating infertility, which can effectively promote embryo implantation rate for infertility patients undergoing in vitro fertilization and embryo transfer (IVF-ET) by improving endometrial receptivity. However, the exact mechanism underlying BSTJD-improved endometrial receptivity has not yet been elucidated.
AIM OF THE STUDY: Krüppel-like factor 4 (KLF4) is an essential transcription factor that regulates endometrial angiogenesis. This study investigates the effect and mechanism of BSTJD on promoting endometrial angiogenesis involved in KLF4.
METHODS: The controlled ovarian hyperstimulation (COH) mouse model was established and treated with BSTJD. Embryo implantation numbers and the changes in uterine morphology were evaluated. Human endometrial microvascular endothelial cells (HEMECs) were treated with BSTJD medicated serum, or adenovirus overexpressing KLF4. Tube formation assay was performed to observe HEMEC tubulogenesis. Mitochondrial function of HEMECs was evaluated. The levels of MMP-9, PCNA, Caspase 3, VEGFA, KLF4, GCN5, and succinylated H3K79 in HEMECs were measured. The KLF4 combined with GCN5 and its succinylation were detected by immunoprecipitation, and their localization was performed for immunofluorescence staining. Chromatin immunoprecipitation assay was performed for KLF4 and succinylated H3K79 enrichments on the VEGFA promoter.
RESULTS: BSTJD promoted endometrial angiogenesis to improve endometrial receptivity, so as to increase the embryo implantation numbers in the COH mice model. BSTJD could coordinate with VEGFA to upregulate KLF4 level, which increased HEMECs proliferation and migration and decreased cell apoptosis via improving mitochondrial function. BSTJD promoted KLF4-GCN5 complex formation via activating the ERK pathway. This complex was recruited to the KLF4-binding site of the VEGFA promoter in HEMECs and transactivated VEGFA expression, leading to endometrial angiogenesis.
CONCLUSIONS: BSTJD improves endometrial receptivity to increase embryo implantation by activating KLF4, which not only promotes angiogenesis through improving mitochondrial function but also strengthens the KLF4-GCN5 interaction to activate VEGFA transcription.
AIM OF THE STUDY: Krüppel-like factor 4 (KLF4) is an essential transcription factor that regulates endometrial angiogenesis. This study investigates the effect and mechanism of BSTJD on promoting endometrial angiogenesis involved in KLF4.
METHODS: The controlled ovarian hyperstimulation (COH) mouse model was established and treated with BSTJD. Embryo implantation numbers and the changes in uterine morphology were evaluated. Human endometrial microvascular endothelial cells (HEMECs) were treated with BSTJD medicated serum, or adenovirus overexpressing KLF4. Tube formation assay was performed to observe HEMEC tubulogenesis. Mitochondrial function of HEMECs was evaluated. The levels of MMP-9, PCNA, Caspase 3, VEGFA, KLF4, GCN5, and succinylated H3K79 in HEMECs were measured. The KLF4 combined with GCN5 and its succinylation were detected by immunoprecipitation, and their localization was performed for immunofluorescence staining. Chromatin immunoprecipitation assay was performed for KLF4 and succinylated H3K79 enrichments on the VEGFA promoter.
RESULTS: BSTJD promoted endometrial angiogenesis to improve endometrial receptivity, so as to increase the embryo implantation numbers in the COH mice model. BSTJD could coordinate with VEGFA to upregulate KLF4 level, which increased HEMECs proliferation and migration and decreased cell apoptosis via improving mitochondrial function. BSTJD promoted KLF4-GCN5 complex formation via activating the ERK pathway. This complex was recruited to the KLF4-binding site of the VEGFA promoter in HEMECs and transactivated VEGFA expression, leading to endometrial angiogenesis.
CONCLUSIONS: BSTJD improves endometrial receptivity to increase embryo implantation by activating KLF4, which not only promotes angiogenesis through improving mitochondrial function but also strengthens the KLF4-GCN5 interaction to activate VEGFA transcription.