# Targeting NRP1 in Endothelial Cells Facilitates the Normalization of Scar Vessels and Prevents Fibrotic Scarring

## TL;DR

This study shows that targeting NRP1 in scar blood vessels can normalize their structure and prevent scarring by reducing abnormal changes in vascular function.

## Contribution

The study introduces a novel NRP1-targeting hydrogel spray to normalize scar vasculature and prevent fibrosis.

## Key findings

- Scar vessels show increased vascular density, branching, and incomplete wall coverage.
- NRP1 inhibition reduces endothelial-to-mesenchymal transition and restores vascular function in mice.
- A hydrogel spray targeting NRP1 effectively prevents fibrotic scarring by promoting vascular normalization.

## Abstract

Current clinical treatments for skin scars primarily reduce vascular density in situ. But, outcomes remain unsatisfactory due to limited understanding of scar vascular structure, endothelial cell (EC) heterogeneity, and functional changes. Through dermatoscopy, scanning electron microscopy, and immunofluorescence staining, our study revealed substantial vascular remodeling in scars, including increased neovascularization density, branching complexity, and incomplete vascular wall coverage. Single‐cell sequencing constructed an EC atlas of scar patients, identifying upregulated ATP synthesis, decomposition, and oxidative phosphorylation in scar ECs—characteristics resembling tumor vasculature. Notably, a subset of ECs with high neuropilin‐1 (NRP1) expression exhibited mesenchymal characteristics. In vitro experiments demonstrated that NRP1 knockdown blocked the transforming growth factor‐beta (TGF‐β)/SMAD family member 2 (SMAD2) signaling pathway and mitigated endothelial‐to‐mesenchymal transition (EndMT). Importantly, NRP1 inhibition reduced EndMT, restored normal vascular function and structure, and prevented scar formation in mice. Based on these findings, a functional hydrogel spray was developed using an NRP1‐targeting peptide, effectively preventing scar formation by promoting vascular normalization.

Scars exhibit vascular abnormal alterations, including upregulated NRP1 expression in endothelial cells, increased vascular density and branching, compromised vessel wall integrity, and incomplete pericyte coverage. Therapeutic targeting of NRP1 through hydrogel spray delivery offers a promising approach to normalize aberrant vasculature and prevent fibrotic scarring.