# HDC/histamine Signaling Axis Drives Macrophage Reprogramming to Promote Angiogenesis in Hindlimb-Ischemic Mice

## TL;DR

This study shows that the HDC/histamine signaling pathway in macrophages promotes blood vessel growth in mice with hindlimb ischemia.

## Contribution

The study identifies HDC+CXCR2+ macrophages and their role in angiogenesis, and introduces a hydrogel treatment for ischemic injury.

## Key findings

- HDC is highly expressed in Ly6C+ macrophages, not endothelial cells, in ischemic tissue.
- Inactivation of HDC disrupts histamine production and impairs macrophage-endothelial cell interactions.
- HA-DA@histamine hydrogel effectively modulates inflammation and promotes angiogenesis in ischemic injury.

## Abstract

Histamine is catalyzed by histidine decarboxylase (HDC), which plays important roles in many physiological and pathological processes, but its role in angiogenesis has not been thoroughly clarified. Here we report that HDC is highly expressed in Ly6C+ macrophages, rather than in endothelial cells using Hdc-GFP transgenic mice with hindlimb ischemia (HLI) mouse model. Given the whole-process promoting effect of macrophages on angiogenesis, a cluster of HDC+CXCR2+ macrophages have been identified by single-cell sequencing technology in ischemic tissue. The inactivation of HDC leads to a lack of histamine and pro-angiogenic factor production in macrophages, inducing a harsh inflammatory microenvironment that is not conducive to the interaction between macrophages and endothelial cells. Moreover, HA-DA@histamine hydrogel has been designed and demonstrated to safely treat ischemic injury by modulating inflammation and angiogenesis. These data highlight the critical roles of HDC/histamine signaling in macrophage differentiation, angiogenesis, and muscle regeneration in the early stage of HLI.