Salvianolic Acid B

Pathologically immature intraplaque neovessels lacking pericyte coverage and structural stability contribute to plaque rupture. Piezo1 activation impairs neovessel maturation by disrupting Ang-1-mediated endothelial-pericyte interactions, weakening neovessel integrity. Danshen decoction (DSD) is a clinically established traditional Chinese medicine formula for atherosclerosis treatment. This study investigates DSD's therapeutic mechanism in promoting neovascular maturation via Piezo1 inhibition.

To investigate the therapeutic effects of DSD on atherosclerotic plaque stability, focusing on its regulation of intraplaque neovessel maturation via Piezo1/YAP/Ang-1 signaling.

UHPLC-Q Exactive Orbitrap mass spectrometry was used to analyze the bioactive components of DSD, and network pharmacology analysis combined with molecular docking was employed to screen and validate the most promising bioactive candidates. ApoE^-/- mice were used to observe the effects of DSD on intraplaque neovessel maturation. H&E and Oil Red O staining were used to evaluate plaque size, distribution, and lipid core content, while immunofluorescence assessed CD31 (endothelial cells) and α-SMA (pericytes) markers. Primary pericytes were then isolated to evaluate the biological impact of DSD on cell viability, apoptosis, and migration in vitro. Piezo1, YAP/TAZ, JNK, Ang-1, and Tie-2 levels in aortic tissue and pericytes were measured by WB, ELISA, and RT-qPCR. We further validated this protein pathway by overactivating Piezo1 with the agonist Yoda1 in pericyte experiments.

DSD markedly reduced aortic plaque area and increased the collagen-to-lipid ratio, enhancing plaque stability in ApoE^-/- mice. Mass spectrometry identified several major bioactive constituents of DSD, including salvianolic acid B, glycyrrhizin, salvianolic acid D, and tanshinone IIA. Network pharmacology and molecular docking analyses linked these compounds to vascular remodeling pathways, and literature-based database mining predicted Piezo1 as a potential target. At the cellular level, DSD promoted pericyte viability, reduced apoptosis, and facilitated migration. At the molecular level, it decreased Piezo1 expression, increased YAP and TAZ phosphorylation, suppressed the expression of c-Jun N-terminal kinase (JNK), and elevated Ang-1/Tie-2 expression. Relative to DSD alone, DSD plus the Piezo1 agonist Yoda1 partially reversed these improvements, evidenced by lower p-YAP/TAZ levels, increased JNK expression, and reduced Ang-1/Tie-2 expression, indicating that DSD's effects on neovessel maturation and plaque stabilization are at least partly mediated through Piezo1 inhibition.

DSD stabilizes atherosclerotic plaques by inhibiting Piezo1, thereby promoting neovessel maturation through enhanced YAP/TAZ phosphorylation, JNK suppression, and Ang-1 upregulation. Limitations of this study include the reliance on a single-batch DSD formulation and the absence of direct co-culture validation for pericyte-endothelial paracrine interactions. Nevertheless, our findings highlight Piezo1 as a potential therapeutic target for mitigating plaque vulnerability.

Myocardial infarction (MI), a leading cause of morbidity and mortality, may be treated by enhancing glycolysis in myocardial microvascular endothelial cells to promote angiogenesis. Salvia miltiorrhiza provides cardioprotection by modulating energy metabolism and angiogenesis. While our previous research identified an optimal proportion (OP) of its active components for myocardial protection, it remains unclear whether this mechanism involves the regulation of endothelial glycolysis to promote angiogenesis.

To clarify the therapeutic mechanism by which OP exerts cardioprotective effects by promoting angiogenesis through the upregulation of myocardial endothelial glycolysis.

In this study, oxygen-glucose deprivation (OGD)-treated H9c2 cells were used to detect glycolysis levels, and OGD-treated short hairpin (sh)-6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase3 (PFKFB3) human umbilical vein endothelial cells (HUVECs), and MI C57BL/6 mice were used to detect glycolysis and angiogenesis.

The results demonstrated that OP could increase glycolysis levels through adenosine 5'-monophosphate-activated protein kinase (AMPK)/PFKFB3, and then activate hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) to promote angiogenesis, improve myocardial histopathological morphology, attenuate myocardial fibrosis, reduce levels of myocardial enzymes, enhance cardiac function, and ultimately exert myocardial protective effects in MI mice.

OP can enhance myocardial glycolysis through AMPK/PFKFB3, and then activate HIF-1α/VEGF/VEGFR2 to promote angiogenesis and serve as a therapy for MI. The preliminary elucidation of the efficacy and therapeutic mechanism of OP in MI provides a methodological basis for the clinical application and drug development of Salvia miltiorrhiza.