Kuanxiong aerosol protects against coronary microvascular dysfunction through improving angiogenesis via HIF-1α-ITGAX axis.

BACKGROUND: Coronary microvascular dysfunction (CMVD) frequently complicates diabetes mellitus and serves as a major driver of cardiovascular morbidity, underscoring the urgent need for innovative therapeutic strategies. Kuanxiong aerosol (KX), a patented botanical formulation of four volatile oils widely used for angina, possesses established vasoprotective and hemodynamic benefits. However, its efficacy and mechanisms in CMVD remain uncharacterized. METHODS: To evaluate the therapeutic potential of KX, both preventive and therapeutic treatment regimens were administered to a db/db mouse model of diabetic CMVD. In vivo therapeutic effects were comprehensively assessed using echocardiography and histopathological analyses. Microvascular perfusion and endothelial barrier function were quantitatively evaluated via Lectin-FITC perfusion and permeability assays.These findings were further corroborated by bulk RNA sequencing, immunofluorescence, and cellular functional assays, while bioinformatics and biochemical analyses systematically revealed the molecular targets and pathways. RESULTS: KX restored coronary microvascular structure and function, promoting neovascularization and conferring both preventive and therapeutic benefits against CMVD in db/db mice. Mechanistically, RNA sequencing and biochemical analyses revealed that KX stabilizes HIF-1α against PHD2-mediated proteasomal degradation. This stabilization enhances HIF-1α transcriptional activity to upregulate ITGAX, which subsequently triggers the VEGF-FAK signaling pathway to drive endothelial proliferation, angiogenesis and tight junction formation. Consequently, the improved microvascular function and stabilized nascent vascular network restore myocardial blood supply, thereby rescuing CMVD. CONCLUSION: KX exerts its therapeutic effects through modulation of the HIF-1α-ITGAX axis, thereby promoting angiogenesis and restoring microvascular integrity and perfusion. These findings establish KX as a promising therapeutic candidate for CMVD and diabetic cardiomyopathy.