Cdc42 has important roles in postnatal angiogenesis and vasculature formation

Yoshida, Yuko; Yamada, Atsushi; Akimoto, Yoshihiro; Abe, Kyōko; Matsubara, Sachie; Hayakawa, Junri; Tanaka, Junichi; Kinoshita, Mitsuhiro; Kato, Tadashi; Ogata, Hiroaki; Sakashita, Akihiko; Mishima, Kenji; Kubota, Yoshiaki; Kawakami, Hayato; Kamijo, Ryutaro; Iijima, Takehiko

doi:10.1016/j.ydbio.2021.05.002

Cited by 9 publications

(8 citation statements)

References 17 publications

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“…In these key target genes of the VEGF signaling pathway, VEGFA and MMP9 are all closely associated with angiogenesis. , SRC also plays an important role in the control of angiogenesis . In addition, the angiogenesis-related genes also include NOS3, MAP2K1, and CDC42. − In the present study, BAI combined with ECH could significantly reverse the mRNA expression of these key genes in the VEGF signaling pathway, especially the better effect of B2-E1 than those of the single component, B1-E1, and B1-E2.…”

Section: Resultssupporting

confidence: 48%

Topical Application of Baicalin Combined with Echinacoside Ameliorates Psoriatic Skin Lesions by Suppressing the Inflammation-Related TNF Signaling Pathway and the Angiogenesis-Related VEGF Signaling Pathway

Chen,

Wang,

Song

et al. 2023

ACS Omega

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Baicalin (BAI), the main active component of Scutellaria baicalensis, has significant anti-inflammatory and antibacterial effects. Echinacoside (ECH), an active component from Echinacea purpurea, has significant antiangiogenesis and antioxidant effects. In previous studies, BAI or ECH has been used for some skin inflammation problems by topical treatment. Psoriasis (PSO) is a common inflammatory skin disease with typical features such as excessive inflammatory response and vascular proliferation in skin lesions. Because of the anti-inflammatory effect of BAI and the antiangiogenic activity of ECH, it is proposed that the combination of BAI and ECH can ameliorate psoriatic skin lesions better than a single component. This study aims to explore the effects and potential mechanisms of BAI combined with ECH on imiquimod (IMQ)-induced psoriatic skin lesions by topical treatment. Transcriptome analysis first showed that the TNF signaling pathway and the VEGF signaling pathway were significantly enriched in IMQ-induced psoriatic skin lesions. Topical application of BAI combined with ECH could ameliorate IMQ-induced skin lesions in mice, especially the better effects of B2-E1 (BAI/ECH = 2:1). Network pharmacology analysis and molecular docking indicated that BAI-treated PSO on the skin by regulating the TNF signaling pathway, and ECH treated PSO on the skin by regulating the VEGF signaling pathway. Meanwhile, the ELISA test and the qPCR assay showed that BAI combined with ECH could inhibit the expression of key cytokines and genes related to the TNF signaling pathway and the VEGF signaling pathway. Zebrafish experiments demonstrated the anti-inflammatory and antiangiogenic effects of BAI combined with ECH and revealed the potential mechanisms associated with regulating the inflammation-related TNF signaling pathway and the angiogenesis-related VEGF signaling pathway. This suggested that BAI combined with ECH may be a promising topical agent to ameliorate psoriatic skin lesions in the future.

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Section: Resultssupporting

confidence: 48%

Topical Application of Baicalin Combined with Echinacoside Ameliorates Psoriatic Skin Lesions by Suppressing the Inflammation-Related TNF Signaling Pathway and the Angiogenesis-Related VEGF Signaling Pathway

Chen,

Wang,

Song

et al. 2023

ACS Omega

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“…Map3k3 is additionally involved in stress-activated protein kinase signaling and regulation of NFkB activation (Ellinger-Ziegelbauer et al , 1997; Yang et al , 2001), and recent studies show interaction with TGFβ signaling in arterial remodelling (Deng et al , 2021a; Deng et al , 2021b). Eight of the other thirteen genes encode components of G protein coupled receptor (GPCR) signaling pathways related to Cdc42 rho kinase that influences cytoskeletal regulation, cell adhesion and migration (Sakabe et al , 2017; Yoshida et al , 2021). Overall, this powerful inter-specific gene expression network analysis provides strong support for PTPN14 interacting with HHT pathway components to regulate vascular cell adhesion, migration, and mechanotransduction, in lung in vivo.…”

Section: Resultsmentioning

confidence: 99%

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

Mamaï

Taylor

et al. 2021

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular condition caused by germline heterozygous loss-of-function mutations of ENG, AVCRL1, and occasionally SMAD4, encoding components of TGFβ/BMP signaling. Telangiectases occur in most HHT patients, and pulmonary, visceral, or cerebral arteriovenous malformations (AVMs) occur in 20-50%, but our understanding of how HHT mutations disrupt downstream signaling pathways causing clinical manifestations, and why some patients suffer more serious sequelae, is incomplete. We previously showed that genetic variation within PTPN14 at rs2936018 associates with the presentation of PAVM in HHT patients. Here we show rs2936018 is a cis-eQTL for PTPN14, with lower expression of the HHT at-risk allele, and that in primary human endothelial cells, PTPN14 physically interacts with the transcription factor, SMAD4, protecting it from ubiquitylation to support higher SMAD4 expression levels. In a panel of 69 lung samples, we find Ptpn14 RNA expression correlates with markers of angiogenesis, lymphangiogenesis, cell-cell interaction, BMP signaling, and rho kinase signaling, indicating preferential expression in endothelial cells. RNAScope in situ hybridization analysis and use of transgenic Ptpn14-reporter mice (Ptpn14.tm1(KOMP)Vlcg) show that Ptpn14 is predominantly but not exclusively expressed in lymphatic and vascular ECs of lung, heart and skin. In lung, Ptpn14, Acvrl1, Eng and SMAD4 expression are tightly correlated as well as with Flt1, Ece1, Sash1, and Mapk3k. Additionally, Ptpn14, Acvrl1, Eng and SMAD4 show strong expression correlation with components of G protein-coupled receptor (GPCR) signaling pathways impacting rho kinase, Cdc42, a regulator of cell migration. We report, for the first time, that in primary human endothelial cells PTPN14 binds SMAD4, as demonstrated by coimmunoprecipitation studies and confirmed by proximity ligation assay. In the nucleus, PTPN14 stabilizes SMAD4, protecting it from ubiquitylation and turnover and potentiating basal transcriptional activity from BMP and TGFβ responsive reporters, whereas in the cytoplasm PTPN14 sequesters phospho-TAZ (pTAZ) leading to TAZ turnover. PTPN14 therefore provides a physical link supporting BMP/ALK-1/SMAD4 signaling while inhibiting YAP/TAZ signaling in ECs to regulate a balance between these two pathways to maintain vascular stability. Polymorphisms in PTPN14 may alter tonic BMP/ALK-1/SMAD4 and TGFβ/TGFβRI/SMAD4 signaling to magnify ligand-mediated responses. In this way, genetic variation within PTPN14 may influence the clinical outcomes of HHT through its action on SMAD4.

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“…A previous study has demonstrated that Cdc42 inhibits myocardial hypertrophy by activating JNK ( 12 ), which promotes c-Jun expression and inhibits the activation of the Tgfb1 promoter ( 20 ). Cdc42 also serves an important role in regulating transcription factor activity ( 10 ). In the present study, in TGF-β1-stimulated MCFs, the protein expression levels of Cdc42, Pak1, JNK and c-Jun were decreased.…”

Section: Discussionmentioning

confidence: 99%

“…Cell division cycle 42 (Cdc42), a member of the Rho-like GTPase family, is an important regulator of actin polymerization and cytoskeletal reorganization ( 8 , 9 ). Cdc42 can regulate transcription factor activity, microtubule dynamics, membrane transport pathways and cell polarity ( 10 ). Furthermore, Cdc42 is an important member of the TGF-β1 non-Smad pathway ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Estrogen inhibits TGF‑β1‑stimulated cardiac fibroblast differentiation and collagen synthesis by promoting Cdc42

Xu,

Wang,

et al. 2024

Mol Med Rep

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17β-estradiol (E2) can inhibit cardiac fibrosis in female patients with heart failure (HF) and activate cell division cycle 42 (Cdc42), however it is unknown whether 17β-estradiol (E2) can ameliorate differentiation and collagen synthesis in TGF-β1-stimulated mouse cardiac fibroblasts (MCFs) by regulating cell division cycle 42 (Cdc42). The present study aimed to investigate the roles of estrogen and Cdc42 in preventing myocardial fibrosis and the underlying molecular mechanisms. An ELISA was used to measure the levels of E2 and Cdc42 in the serum of patients with heart failure (HF), and western blotting was used to measure the expression levels of Cdc42 in TGF-β1-stimulated immortalized MCFs. MCFs were transfected with a Cdc42 overexpression (OE) lentivirus or small interfering RNA (siRNA), or treated with a Cdc42 inhibitor (MLS-573151), and the function of Cdc42 was assessed by western blotting, immunofluorescence staining, reverse transcription-quantitative PCR and dual-luciferase reporter assays. Western blotting and immunofluorescence staining were performed to verify the protective effect of E2 on TGF-β1-stimulated MCFs, and the association between the protective effect and Cdc42. The results demonstrated that Cdc42 levels were increased in the serum of patients with HF and were positively correlated with the levels of E2; however, Cdc42 levels were decreased in TGF-β1-stimulated MCFs. Cdc42 inhibited MCF differentiation and collagen synthesis, as indicated by the protein expression of α-smooth muscle actin, collagen I and collagen III. Mechanistically, Cdc42 inhibited the transcription of TGF-β1 by promoting the expression of p21 (RAC1)-activated kinase 1 (Pak1)/JNK/c-Jun signaling pathway proteins and inhibiting the activity of the Tgfb1 gene promoter. In addition, E2 inhibited the differentiation and collagen synthesis of TGF-β1-stimulated MCFs, and promoted the protein expression of Pak1, JNK and c-Jun, consistent with the effects of Cdc42, whereas the effects of E2 were abolished when Cdc42 was knocked down. The aforementioned findings suggested that E2 could inhibit differentiation and collagen synthesis in TGF-β1-stimulated MCFs by regulating Cdc42 and the downstream Pak1/JNK/c-Jun signaling pathway.

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Cdc42 has important roles in postnatal angiogenesis and vasculature formation

Cited by 9 publications

References 17 publications

Topical Application of Baicalin Combined with Echinacoside Ameliorates Psoriatic Skin Lesions by Suppressing the Inflammation-Related TNF Signaling Pathway and the Angiogenesis-Related VEGF Signaling Pathway

Topical Application of Baicalin Combined with Echinacoside Ameliorates Psoriatic Skin Lesions by Suppressing the Inflammation-Related TNF Signaling Pathway and the Angiogenesis-Related VEGF Signaling Pathway

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

Estrogen inhibits TGF‑β1‑stimulated cardiac fibroblast differentiation and collagen synthesis by promoting Cdc42

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