# Hepatic vein-derived factors may affect pulmonary arteriovenous malformations after single ventricle palliation by modulating vascular cell behavior

## TL;DR

This study explores how plasma from different veins affects blood vessel growth in infants with heart disease, shedding light on a complication called pulmonary arteriovenous malformations.

## Contribution

The study introduces a novel in vitro arteriovenous model to compare plasma effects on angiogenesis and identifies distinct proteomic profiles from different venous sources.

## Key findings

- SVC plasma showed a pro-angiogenic profile compared to hepatic vein plasma in vitro.
- Hepatic vein plasma contained proteins linked to vascular stability and cell adhesion.
- The study highlights the role of extracellular mechano-transduction in PAVM development.

## Abstract

Pulmonary arteriovenous malformations (PAVM) are a major surgical complication of univentricular heart therapy, significantly limiting patient survival. Interruption of hepatic venous drainage into the lungs has been long hypothesized to play a critical role in PAVM development by angiogenesis modulation. To understand human plasma role on PAVM development, we conducted a prospective study analyzing paired plasma samples from superior vena cava (SVC) and hepatic vein (HV) origin from 10 infants with congenital heart disease. Two and three dimensional in vitro arteriovenous models were implemented to compare the angiogenic potential of SVC and HV plasma, alongside untargeted shotgun proteomic profiling. Compared to HV, SVC plasma exhibited a pro-angiogenic profile in vitro. SVC proteome was enriched with pro-angiogenic S100 calcium-binding family proteins (S100A7/A8/A9/P). In contrast, HV plasma had unique expression of actin binding proteins (profilin 1/filamin A/actinin alfa 1), and upregulation of pathways associated with vascular stability and cell adhesion maintenance, suggesting a plausible counteracting role to SVC. Our results emphasize the importance of considering not only angiogenesis, but also extracellular mechano-transduction and vascular tone regulation in PAVM pathogenesis; and highlights the value of in vitro arteriovenous modeling to bridge the gap towards PAVM understanding and advancement of future therapeutical alternatives.

The online version contains supplementary material available at 10.1038/s41598-025-25523-1.