Targeting soluble epoxide hydrolase promotes osteogenic–angiogenic coupling via activating SLIT3/HIF‐1α signalling pathway

Cell Proliferation · 10 authors, 3 centres

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TL;DR

This preclinical study investigated the effects of the sEH inhibitor TPPU on the coupling of angiogenesis and osteogenesis using human cell co-cultures and mouse models. The central result is that TPPU enhances osteogenic–angiogenic coupling and bone repair by upregulating hDPSC-derived SLIT3 to activate the ROBO1/YAP1/HIF-1α pathway, leading to increased type H vessel formation.

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The study used an in vitro co-culture model of human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), alongside in vivo mouse models of long bone growth and calvarial defect repair, to examine the effects of the sEH inhibitor TPPU. Results showed that TPPU increased cell proliferation, angiogenesis, and osteogenic differentiation in co-cultures, and enhanced type H vessel formation and bone repair in mice. Mechanistically, TPPU upregulated SLIT3 expression in hDPSCs, which activated the ROBO1/YAP1/HIF-1α signaling pathway in endothelial cells. Knockdown experiments confirmed that this pathway is essential for TPPU's effects. Limitations include the use of specific human cell types and animal models, requiring further investigation for direct human therapeutic application.

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other

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preclinical research

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ORIGINAL PAPER

PMC10334284

Targeting soluble epoxide hydrolase promotes osteogenic–angiogenic coupling via activating SLIT3/HIF‐1α signalling pathway

Cell Proliferation

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ABSTRACT

Abstract Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross‐talk between co‐cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co‐cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31 hi EMCN hi endothelial cells (ECs) and SLIT3 and HIF‐1α expression levels in co‐cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif‐1α in HUVECs impaired the formation of CD31 hi EMCN hi ECs and reversed TPPU‐induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs‐derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF‐1α signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair.

CITATION EXPORT

Lu Gao, Weixian Chen, Lijun Li et al.. Targeting soluble epoxide hydrolase promotes osteogenic–angiogenic coupling via activating SLIT3/HIF‐1α signalling pathway. Cell Proliferation. (2023). https://doi.org/10.1111/cpr.13403

AUTHORS

10 · 3 CENTRES

Lu Gao, Weixian Chen, Lijun Li, Juanjuan Li, Wenyao Kongling, Yaoyang Zhang, Xueping Yang, Yanrong Zhao, Jie Bai, Fu Wang

1 School of Stomatology, Dalian Medical University, Dalian, China
2 Academician Laboratory of Immune and Oral Development & Regeneration, Dalian Medical University, Dalian, China
3 The Affiliated Stomatological Hospital of Dalian Medical University School of Stomatology, Dalian, China