Andrographolide Promotes Interaction Between Endothelin-Dependent EDNRA/EDNRB and Myocardin-SRF to Regulate Pathological Vascular Remodeling

Hu, Wangming; Wu, Xiao; Wang, Zheng; Guo, Qiru; Chen, Zixian; Zhu, Song; Zhang, Haidi; Huo, Jiuyuan; Zhang, Lingling; Zhou, Xin; Yang, Lan; Xu, Huan; Shi, Lei; Wang, Yong

doi:10.3389/fcvm.2021.783872

Cited by 4 publications

(11 citation statements)

References 39 publications

(44 reference statements)

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“…PDA, a derivative of andrographolide, has been clinically used for the therapeutic treatment of inflammatory diseases. Our previous studies demonstrated that andrographolide plays a critical role in maintaining vascular homeostasis, as well as in regulating smooth muscle cell phenotypic switch-dependent pathological vascular remodeling [ 26 , 27 ]. However, whether PDA is involved in regulating endothelial barrier repair in pathological vascular remodeling is not known.…”

Section: Discussionmentioning

confidence: 99%

“…The mouse carotid arteries were fixed with 4% paraformaldehyde overnight at 4 °C and embedded in paraffin, and 5 μm thick slides were collected. H&E staining was performed as previously described [ 27 ]. For IHC staining, antigen retrieval was performed with citric acid treatment at 98 °C for 5 to 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…The spheroid sprouting assay was performed as described previous [ 27 ]. Methylcellulose solution was prepared by dissolving 6 g methylcellulose (sigma) in 250 mL of prewarmed serum-free medium, and 250 mL of DMEM containing 10% serum was added.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies demonstrated that andrographolide is critical to maintaining gastric vascular homeostasis, as well as to regulating pathological vascular remodeling [ 26 , 27 ]. Potassium dehydroandrograpolide succinate (PDA), a derivative of andrographolide, has been clinically used for therapeutic treatment of inflammatory diseases [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Potassium Dehydroandrograpolide Succinate Targets NRP1 Mediated VEGFR2/VE-Cadherin Signaling Pathway to Promote Endothelial Barrier Repair

Wang

et al. 2023

IJMS

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Impairment of vascular endothelial integrity is associated with various vascular diseases. Our previous studies demonstrated that andrographolide is critical to maintaining gastric vascular homeostasis, as well as to regulating pathological vascular remodeling. Potassium dehydroandrograpolide succinate (PDA), a derivative of andrographolide, has been clinically used for the therapeutic treatment of inflammatory diseases. This study aimed to determine whether PDA promotes endothelial barrier repair in pathological vascular remodeling. Partial ligation of the carotid artery in ApoE-/- mice was used to evaluate whether PDA can regulate pathological vascular remodeling. A flow cytometry assay, BRDU incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay and Matrigel-based tube formation assay were performed to determine whether PDA can regulate the proliferation and motility of HUVEC. A molecular docking simulation and CO-immunoprecipitation assay were performed to observe protein interactions. We observed that PDA induced pathological vascular remodeling characterized by enhanced neointima formation. PDA treatment significantly enhanced the proliferation and migration of vascular endothelial cells. Investigating the potential mechanisms and signaling pathways, we observed that PDA induced endothelial NRP1 expression and activated the VEGF signaling pathway. Knockdown of NRP1 using siRNA transfection attenuated PDA-induced VEGFR2 expression. The interaction between NRP1 and VEGFR2 caused VE-Cad-dependent endothelial barrier impairment, which was characterized by enhanced vascular inflammation. Our study demonstrated that PDA plays a critical role in promoting endothelial barrier repair in pathological vascular remodeling.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potassium Dehydroandrograpolide Succinate Targets NRP1 Mediated VEGFR2/VE-Cadherin Signaling Pathway to Promote Endothelial Barrier Repair

Wang

et al. 2023

IJMS

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“…The spheroid sprouting assay was performed as described previously (37). Methylcellulose solution was prepared by dissolving 6 g methylcellulose (sigma) in 250 ml prewarmed serum-free medium, and 250 ml complete medium was added.…”

Section: Spheroid Sprouting Assaymentioning

confidence: 99%

Andrographolide suppresses hypoxia-induced embryonic hyaloid vascular system development through HIF-1a/VEGFR2 signaling pathway

Guo¹,

Wang²,

Wu³

et al. 2023

Front. Cardiovasc. Med.

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IntroductionOcular abnormalities and the development of retinal vasculature may cause postnatal retinopathy. In the past decade, tremendous progress has been made in identifying the mechanisms that regulate retina vasculature. However, the means of regulating embryonic hyaloid vasculature development is largely unknown. This study aims to determine whether and how andrographolide regulates embryonic hyaloid vasculature development.MethodsMurine embryonic retinas were used in this study. Whole mount isolectin B4 (IB4) staining, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and immunofluorescence staining (IF) were performed to determine whether andrographolide is critical for embryonic hyaloid vasculature development. BrdU incorporation assay, Boyden chamber migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay were performed to evaluate whether andrographolide regulates the proliferation and migration of vascular endothelial cells. Molecular docking simulation and Co-immunoprecipitation assay were used to observe protein interaction.ResultsHypoxia conditions exist in murine embryonic retinas. Hypoxia induces HIF-1a expression; high-expressed HIF-1a interacts with VEGFR2, resulting in the activation of the VEGF signaling pathway. Andrographolide suppresses hypoxia-induced HIF-1a expression and, at least in part, interrupts the interaction between HIF-1a and VEGFR2, causing inhibiting endothelial proliferation and migration, eventually inhibiting embryonic hyaloid vasculature development.ConclusionOur data demonstrated that andrographolide plays a critical role in regulating embryonic hyaloid vasculature development.

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Dissecting the Genetic Architecture of Intracranial Aneurysms

Adkar,

Lynch,

Choi

et al. 2023

Preprint

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Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed largely to the genetic risk of smoking exposure and hypertension. However, the relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear. Methods: We performed a genome-wide association study in the Million Veteran Program testing association of roughly 25 million DNA variants with unruptured IA (3,165 cases and 592,927 controls) in veterans of European, African, and Hispanic ancestries. This was meta-analyzed with publicly available summary statistics to yield a final cohort of 15,438 cases and 1,183,973 controls. Candidate causal genes were prioritized through expression quantitative trait loci colocalization, fine-mapping transcriptome wide association studies, and multi-trait colocalization. We constructed a cerebrovascular single nucleus RNA sequencing (snRNA-seq) dataset and integrated IA summary statistics to prioritize candidate causal cell types. We then constructed a polygenic risk score to identify patients at greater risk of developing IA. Results: We identified five novel loci association with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 16 candidate causal genes. Amongst other cardiovascular traits, we found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm, and we identified 13 IA risk loci that colocalize with aneurysmal, atherosclerotic, and blood pressure traits. Integration of an IA gene set with human cerebrovascular snRNA-seq data revealed significant association with matrix-producing pericytes, smooth muscle cells (SMCs), and other mural subtypes. In addition, gene expression analysis revealed enrichment of several candidate genes within SMCs and pericytes. Finally, a high polygenic risk score (PRS) was significantly associated with IA across European (OR: 1.87, CI: 1.61-2.17, P = 8.8 x 10-17), African (OR: 1.62, CI: 1.19-2.15, P = 1.2 x 10-3), and Hispanic (OR: 2.28, CI: 1.47-3.38, P = 1.0 x 10-4) ancestries. Conclusion: Here, we identify five novel loci associated with IA. Integration of summary statistics with cerebrovascular snRNA-seq reveals association of cell-types involved in matrix production. We constructed and validated a PRS that predicts IA, while controlling for demographic variables including smoking status, sex, and blood pressure. Taken together, our findings suggest that an intrinsic deficit in matrix production and vascular integrity may drive IA pathogenesis independent of systemic hypertension and smoking exposure.

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Andrographolide Promotes Interaction Between Endothelin-Dependent EDNRA/EDNRB and Myocardin-SRF to Regulate Pathological Vascular Remodeling

Cited by 4 publications

References 39 publications

Potassium Dehydroandrograpolide Succinate Targets NRP1 Mediated VEGFR2/VE-Cadherin Signaling Pathway to Promote Endothelial Barrier Repair

Potassium Dehydroandrograpolide Succinate Targets NRP1 Mediated VEGFR2/VE-Cadherin Signaling Pathway to Promote Endothelial Barrier Repair

Andrographolide suppresses hypoxia-induced embryonic hyaloid vascular system development through HIF-1a/VEGFR2 signaling pathway

Dissecting the Genetic Architecture of Intracranial Aneurysms

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