Tetrandrine promotes angiogenesis via transcriptional regulation of VEGF-A.

Angiogenesis is crucial for tissue damage repair in ischemic cardiovascular diseases. Vascular endothelial growth factor A (VEGF-A) acts as a vital mediator in angiogenesis. In this study, tetrandrine (Tet) was found from 23 herbal chemicals to increase VEGF-A mRNA expression in H9c2 cells and the effect was confirmed in freshly isolated neonatal rat cardiomyocytes. The effect of Tet on VEGF-A expression and the possible mechanism were investigated. Tet treatment increased de novo VEGF-A mRNA synthesis and did not affect VEGF-A mRNA stability. The circulating chromosome conformation capture (4C) experiments indicated that Tet enhanced VEGF-A transcription by targeting a regulatory element beyond the 2.6 kb region of the translation start site. Tet augmented the angiogenic activities of endothelial cells. It also enhanced blood flow restoration and capillary vessel density following ischemic limb injury associated with an escalation of VEGF-A expression. Moreover, in myocardial infarction (MI) model Tet treatment elevated neovascularization, reduced infarction size, and improved heart function via upregulating VEGF-A levels. Our results suggested that Tet increased VEGF-A transcription through a novel mechanism that likely involves a distant regulatory element and may be useful for therapeutic angiogenesis for ischemic diseases.