Danggui polysaccharides inhibit the PI3K/AKT pathway and hinder smooth muscle cell proliferation and migration
Coronary artery disease (CAD) is one of the most common types of cardiovascular diseases, with a high incidence rate and mortality. Percutaneous coronary intervention (PCI) is a very important minimally invasive treatment method for coronary artery disease (CAD). PCI can effectively improve coronary blood flow, reduce angina, and greatly improve patients’ quality of life. However, the high incidence of vascular restenosis (RS) after angioplasty often affects its long-term treatment effectiveness. Previous studies have shown that the proliferation and migration of vascular smooth muscle cells (VSMCs) are key factors in the development of vascular restenosis after angioplasty. After endothelial injury, VSMCs in the intima are transformed from contractile to synthetic under the action of various growth factors, cytokines, and inflammatory mediators, and migrate towards the subendometrium. Overproliferation is a key step in the formation of neointima. Therefore, effectively inhibiting VSMC proliferation and migration has become a key focus in the prevention and treatment of vascular restenosis. Danggui polysaccharides are the main bioactive components of traditional Chinese medicine Danggui, which play important roles in anti-inflammatory, anti-tumor, and immune regulation. However, the anti RS effect of Angelica polysaccharides has not been reported yet. This experiment used Angelica sinensis polysaccharides to treat human vascular smooth muscle cells (hVSMCs), observed the proliferation, migration, and invasion status of VSMCs, and explored the possible molecular mechanism of Angelica sinensis polysaccharides regulating VSMC function, providing strategies for early intervention and treatment of vascular restenosis.

Traditional Chinese medicine active substances have been used for a long time to prevent vascular restenosis after PCI due to their minimal side effects. As the main active ingredient of Angelica sinensis, polysaccharides have various important biological activities such as antioxidant, anti-tumor, hematopoietic regulation, immune regulation, and neuroprotection. Research has found that Angelica polysaccharides can improve the bone marrow hematopoietic microenvironment by regulating bone marrow hematopoietic stem cells. In addition, Angelica polysaccharides can improve acute liver injury in rats caused by excessive acetaminophen (APAP) by inhibiting oxidative stress and hepatocyte apoptosis. Mechanistically, the biological activity of Angelica sinensis polysaccharides can be achieved by regulating multiple signaling pathways. Danggui polysaccharides regulate hypoxia induced apoptosis and autophagy of rat neural stem cells by downregulating BNIP3 and activating mTOR and Notch signaling pathways. The latest research has found that Angelica polysaccharides inhibit the growth, migration, and invasion of cervical cancer Hela cells by regulating the p38 signaling pathway. However, the effects and potential mechanisms of Angelica polysaccharides on the proliferation of vascular smooth muscle cells and the repair of damaged blood vessels have not been studied. In this study, we found that Angelica polysaccharide serum significantly inhibited Ang II and HB EGF induced proliferation, migration, and invasion of hVSMCs in vitro. And further demonstrate that the inhibitory effect of Angelica sinensis polysaccharide serum on hVSMC proliferation, migration, and invasion is achieved by inhibiting protein activity in the PI3K/AKT signaling pathway.
It is well known that Ang Ⅱ is a known pathogenic factor for atherosclerosis, hypertension and vascular restenosis. According to reports, high levels of HB-EGF are associated with a high risk of in stent restenosis. The results of this study showed that Ang II and HB EGF can significantly induce the proliferation, migration, and invasion of hVSMCs. It is worth noting that Angelica polysaccharides can significantly reduce the proliferation, migration, and invasion levels of hVSMCs induced by Ang II and HB-EGF. In addition, some migration regulatory proteins, including cell adhesion molecules ICAM1, VCAM-1, MMP2, and MMP9, have been reported as important regulatory proteins for abnormal VSMC migration. MMPs， Especially MMP2 and MMP9 are rapidly activated after vascular injury. The results of this study indicate that Angelica polysaccharide serum can inhibit the expression of MMP2 and MMP9 induced by Ang II and HB-EGF stimulation.
The PI3K/AKT signaling pathway extensively regulates cellular immunity, proliferation, differentiation, and apoptosis processes. Previous studies have reported that the PI3K/AKT signaling pathway plays an important role in activating hVSMC proliferation and migration, as well as in neointimal hyperplasia after vascular injury. The activation of the PI3K/AKT signaling pathway can lead to restenosis of blood vessels within the stent. On the contrary, the nanoparticle eluting stent containing AKT1 siRNA can effectively alleviate restenosis within the stent. In the arterial model of common artery stent implantation, gefitinib coated balloon can inhibit VSMC proliferation and promote cell apoptosis by suppressing the PI3K/AKT signaling pathway. Experiments have also found that stimulating human pulmonary artery VSMCs with PDGF can activate PI3K. PI3K regulates ribosome S6 protein by phosphorylating the downstream ribosomal protein p7OS6K of AKT, thereby promoting VSMC proliferation and migration. IGF-1 can effectively inhibit this process, demonstrating that PDGF induces VSMC proliferation and migration in a PI3K dependent manner. Zhou et al. simulated the mechanical stimulation of VSMCs after stent implantation in vitro and found that loading mouse VSMCs with 5% and 20% potential for 6 hours could activate the PI3K/AKT signaling pathway and downstream GSK. In addition, ginsenoside R1 inhibits VSMC proliferation, migration, and neointimal hyperplasia through the PI3K/Akt signaling pathway. This study found that the PI3K/Akt signaling pathway agonist IGF-1 can reverse the inhibitory effect of Angelica sinensis polysaccharide serum on hVSMC proliferation, migration, and invasion.
In summary, Angelica polysaccharide serum can successfully inhibit the proliferation, migration, and invasion of hVSMCs stimulated by Ang II and HB EGF. One of its important mechanisms of action is to reduce the activity of the PI3K/Akt signaling pathway. This study provides a new therapeutic strategy for anti vascular restenosis.