Cinnamaldehyde accelerates wound healing by promoting angiogenesis via up-regulation of PI3K and MAPK signaling pathways

The bark of Cinnamomum cassia (C. cassia) has been used for the management of coronary heart disease (CHD) and diabetes mellitus. C. cassia may target the vasculature, as it stimulates angiogenesis, promotes blood circulation and wound healing. However, the active components and working mechanisms of C. cassia are not fully elucidated. The Shexiang Baoxin pill (SBP), which consists of seven medicinal materials, including C. cassia etc., is widely used as a traditional Chinese patent medicine for the treatment of CHD. Here, 22 single effective components of SBP were evaluated against the human umbilical vein endothelial cells (HUVECs). We demonstrated that in HUVECs, cinnamaldehyde (CA) stimulated proliferation, migration, and tube formation. CA also activated the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Furthermore, the secretion of vascular endothelial growth factor (VEGF) from HUVECs was increased by CA. In vivo, CA partially restored intersegmental vessels in zebrafish pretreated with PTK787, which is a selective inhibitor for vascular endothelial growth factor receptor (VEGFR). CA also showed pro-angiogenic efficacy in the Matrigel plug assay. Additionally, CA attenuated wound sizes in a cutaneous wound model, and elevated VEGF protein and CD31-positive vascular density at the margin of these wounds. These results illustrate that CA accelerates wound healing by inducing angiogenesis in the wound area. The potential mechanism involves activation of the PI3K/AKT and MAPK signaling pathways. Such a small non-peptide molecule may have clinical applications for promoting therapeutic angiogenesis in chronic diabetic wounds and myocardial infarction.