Hepatic Arterial Flow-Induced Portal Tract Fibrosis in Portal Hypertension: The Role of VCAM-1 and Osteopontin-Expressing Macrophages.

BACKGROUND & AIMS: The liver undergoes significant hemodynamic changes during surgery, transplantation, or cirrhosis with portal hypertension (PH). The hepatic artery buffer response (HABR), which compensates for reduced portal venous flow by increasing hepatic artery (HA) flow, is hypothesized to induce pathological portal tract remodeling. This study investigates the molecular mechanisms underlying this process.

METHODS

PH was induced in Sprague-Dawley rats via partial portal vein ligation (PPVL). Structural evaluation (micro computed tomography [microCT]), immune cell profiling, hemodynamic measurements, and transcriptomic analysis in macrophages from sham or PPVL rats were conducted.

RESULTS

MicroCT revealed decreased portal vein flow and increased HA flow correlated with portal pressure (r = 0.799; P < .01). A 2-fold increase in portal tract fibrosis (P < .001) was observed with increased alpha smooth muscle actin (α-SMA)+ myofibroblasts in PPVL rats. CD68+ macrophages peaked at 10 days post-PPVL, and their depletion significantly reduced fibrosis (P < .001), indicating critical roles of macrophages in portal tract remodeling. Vascular cell adhesion molecule 1 (VCAM-1) was elevated in HA endothelium and portal fibroblasts (PFs); VCAM-1 neutralization reduced collagen accumulation (P < .05), CD68+ macrophages (46.3%; P < .01), and CD3+ T cells (18%; P < .05). Macrophage-conditioned medium increased VCAM-1 in PFs (8-fold; P < .001) and enhanced PF migration, whereas VCAM-1 knockdown reduced this effect (P < .01). Single-cell RNA sequencing data (GSE171904) and RNA-fluorescence in situ hybridization revealed increased interactions between Osteopontin (Spp1)+ macrophages and PFs, with Spp1+ macrophages driving fibrosis. Spp1 knockdown in macrophages co-culture reduced PF fibrogenic markers, whereas recombinant SPP1 upregulated Col1a1, Fn1, and Acta2 expression in PFs.

CONCLUSIONS

Increased VCAM-1 in arterial endothelial cells and PFs facilitates the recruitment of Spp1+ macrophages, which drive HA flow-mediated vascular remodeling and portal tract fibrosis. These findings highlight arterial flow-induced fibrosis as a key mechanism in PH, potentially contributing to disease progression and decompensation.