Differential action of pro-angiogenic and anti-angiogenic components of Danhong injection in ischemic vascular disease or tumor models

Zihao Chen,John Owoicho Orgah,Xiumei Gao,Haixin Liu,Rongrong Chen,Shuang He,Jie Ren,Tiechan Zhao,Peng Zhang,Zhenzuo Jiang,Yuefei Wang,Yan Zhu,Li Peng

doi:10.1186/s13020-021-00557-5

Abstract

ObjectiveWe investigate the chemical basis and mechanism of angiogenesis regulation by a multicomponent Chinese medicine Danhong injection (DHI).MethodsDHI was fractionated and screened for angiogenesis activities by in vitro tube formation and migration assays. The composition of DHI components was determined by UPLC. The effects of the main active monomers on angiogenesis-related gene and protein expression in endothelial cells were determined by qPCR and Western blotting analyses. Mouse hind limb ischemia and tumor implant models were used to verify the angiogenesis effects in vivo by Laser Doppler and bioluminescent imaging, respectively.ResultsTwo distinct chemical components, one promoting (pro-angiogenic, PAC) and the other inhibiting (anti-angiogenic, AAC) angiogenesis, were identified in DHI. PAC enhanced angiogenesis and improved recovery of ischemic limb perfusion while AAC reduced Lewis lung carcinoma growth in vivo in VEGFR-2-Luc mice. Among the PAC or AAC monomers, caffeic acid and rosmarinic acid upregulated TSP1 expression and downregulated KDR and PECAM expression. Caffeic acid and rosmarinic acid significantly decreased while protocatechuic aldehyde increased CXCR4 expression, which are consistent with their differential effects on EC migration.ConclusionsDHI is capable of bi-directional regulation of angiogenesis in disease-specific manner. The pro-angiogenesis activity of DHI promotes the repair of ischemic vascular injury, whereas the anti-angiogenesis activity inhibits tumor growth. The active pro- and anti-angiogenesis activities are composed of unique chemical combinations that differentially regulate angiogenesis-related gene networks.

Highlights

Angiogenesis is a fundamental process of normal development, including various pathophysiologies such as ischemic heart disease, atherosclerosis, limb disease, and cancer [1]
We found that the Danhong injection (DHI) active principles Protocatechuic aldehyde (PAl) and Sal C played a major role in promoting angiogenesis, while Caffeic acid (CA) and Rosmarinic acid (RA) had the effect of inhibiting angiogenesis
We conclude that DHI, a widely used compound Chinese patent medicine, contained both pro-and anti-angiogenesis components that compose different chemical combinations

Summary

Introduction

Angiogenesis is a fundamental process of normal development, including various pathophysiologies such as ischemic heart disease, atherosclerosis, limb disease, and cancer [1]. Angiogenesis has the potential to rescue early ischemic myocardium and is essential for long-term left. He et al Chinese Medicine (2022) 17:4 ventricular remodeling to prevent heart failure [2, 3]. Anti-angiogenic therapy can reprogram the tumor immune microenvironment and prune the blood vessel, which is necessary for tumor growth and metastasis [4]. Inhibition of angiogenesis has become a common target of many cancer chemo-preventive agents [5]. More than 10 approved anti-angiogenic tyrosine kinase inhibitors for treating patients with advanced cancers [6]

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Conclusion