Targeting the tyrosine kinase Src in endothelium attenuates inflammation and atherogenesis induced by disturbed flow

Background and purpose: Previous studies have shown that Src can regulate inflammation and tumour progression. However, the mechanisms by which Src regulates the inflammatory response of vascular endothelium and atherogenesis are currently poorly understood. This study aimed to investigate the role of Src in endothelial inflammation and atherogenesis, as well as the underlying mechanisms.

Experimental approach: Real-time quantitative PCR was used to measure the mRNA levels of inflammatory genes. The phosphorylation and localization of proteins were examined using western blotting and immunofluorescence, respectively. The level of p-Src Y416 in mouse endothelium was directly determined using en face staining. Endothelial-specific knockdown of Src was achieved by tail vein injection of AAV-sgSrc in apoE^-/-; Cas9^LSL/LSL; Cdh5-cre mice. Atherosclerosis was induced by partial ligation of the carotid artery.

Key results: Oscillatory shear stress (OSS) promotes the phosphorylation of Src at Y416 in endothelial cells, and Piezo1 is required for this regulatory process. Overexpression of constitutively active Src promotes endothelial inflammation, as well as phosphorylation of STAT3 (at Y705) and its nuclear translocation. Endothelial inflammation induced by OSS was abolished by the Src Inhibitor dasatinib or si-Src. Dasatinib, when administered orally, reduced endothelial inflammation and plaque formation in apoE^-/- mice induced by partial carotid artery ligation. Additionally, plaque formation was decreased in the ligated left carotid artery of mice with endothelial-specific Src knockdown.

Conclusion and implications: Disturbed flow promotes endothelial inflammation and atherogenesis through the Piezo1-Src-Stat3 pathway. Therefore, inhibiting Src in endothelial cells could be a promising therapeutic strategy to treat atherogenesis.

Src; atherosclerosis; endothelial inflammation; oscillatory shear stress.