Endothelial Tgfbr2 Deficiency Ameliorate Liver Fibrosis Through Regulating Angiocrine Signalling and Macrophage Accumulation

ABSTRACT Background & Aims Transforming growth factor (TGF)‐β signalling plays an indispensable role in promoting the activation of hepatic stellate cells and inducing epithelial‐mesenchymal transition of hepatocytes during liver fibrosis. Liver sinusoidal endothelial cells (LSECs) undergo capillarisation and promote inflammatory responses following liver injury. Here, we investigated the role of TGF‐β signalling in LSECs during liver fibrosis. Methods Single‐cell RNA‐sequencing (scRNA‐seq) datasets from healthy individuals and patients with cirrhosis were analysed to evaluate the expression of TGF‐β signalling related genes. Endothelial cell‐specific Tgfbr2 ‐knockout mice were generated and experimental liver fibrosis was induced by carbon tetrachloride injection or choline‐deficient high‐fat diet. Liver fibrosis was evaluated by qPCR, western blotting, histology and immunostaining. Primary LSECs were isolated and gene expression was analysed by RNA sequencing. Hepatic inflammation was assessed by qPCR, immunostaining and flow cytometry. Results ScRNA‐seq analysis based on GSE136103 showed TGFBR2 is elevated in LSECs from cirrhotic patients compared to healthy controls. LSEC‐specific Tgfbr2 depletion ameliorated injury‐induced LSEC capillarisation and endothelial‐to‐mesenchymal transition. RNA sequencing revealed that Tgfbr2 deficiency downregulated chemokine expression and reshaped angiocrine signalling in LSECs. Endothelial‐specific Tgfbr2 deletion inhibited pro‐inflammatory monocyte recruitment and attenuated hepatic inflammation during liver fibrosis. Furthermore, Tgfbr2 deletion in LSECs inhibited macrophage chemotaxis in vitro. Conclusions Endothelial TGF‐β signalling aggravates injury‐induced liver fibrosis by promoting LSECs capillarisation, EndMT and proinflammatory monocyte recruitment. These findings show the potential of targeting TGFBR2 in LSECs to control liver fibrotic diseases.