Abstract
Background: The DEAD-box family plays a crucial role in tumorigenesis and immune responses. Our previous research has identified an association between the dysfunction of DEAD-box RNA helicase 24 (DDX24) and a specific type of vascular malformation. However, the role and mechanism of DDX24 in vascular development remains unclear.Research questions: What is the role of DDX24 in regulating vascular smooth muscle cell (VSMC) function and embryonic vascular development? Aims: Our aim is to investigate the function and regulatory mechanism of DDX24 in embryonic vascular development. Methods: Cardiomyocyte/VSMC-specific Ddx24 knockout mice were generated by crossing Tagln -Cre mice with Ddx24 flox/flox transgenic mice. Stereomicroscopic photography and immunofluorescence staining were used to examine the development of blood vessels. Flow cytometry and cell proliferation assays were employed to assess the effect of DDX24 on VSMC functions. RNA sequencing and RNA immunoprecipitation were performed to uncover the downstream target of DDX24. Additionally, RNA pull-down and RNA stability experiments were conducted to elucidate the regulatory mechanism. Results: Cardiomyocyte/VSMC-specific Ddx24 knockout mice died before embryonic day 13.5 and exhibited defects in embryonic vascular formation and vascular remodeling in extraembryonic tissues. Ddx24 knockdown led to the suppression of VSMC proliferation through cell cycle arrest, likely due to increased DNA damage. DDX24 protein was found to bind to and stabilize the mRNA of FA complementation group A ( FANCA ), a gene that responds to DNA damage. Depletion of FANCA also affected cell cycle and DNA repair in VSMCs. Overexpression of FANCA successfully rescued the alterations induced by DDX24 deficiency. Conclusion: Our study illuminates the role of DDX24 in VSMC-mediated vascular development, suggesting a potential therapeutic target for diseases associated with VSMC dysfunction.
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