Potential anti-arteriovenous malformations effect of sirolimus on angiogenesis induced by maxillofacial venous hypertension

Background: This study aimed to explore the possible role and mechanism of venous hypertension (VH) in the occurrence and development of arteriovenous malformations (AVMs) and to study the therapeutic effect of VH regulation on AVMs to provide insight into AVM pathogenesis and explore new treatments. Methods: Maxillofacial VH models were established by cervical vascular anastomosis. Osteogenesis and angiogenesis in the model rats were analysed by imaging and histology, and the inhibitory effects of intraperitoneal (ip) sirolimus injection on angiogenesis were detected. The effect of sirolimus on the biological behaviour of human umbilical vein endothelial cells (HUVECs) cultured in vitro and mechanism of sirolimus were detected by cytology. Result: The local microvessel density increased, the vessels showed tortuous dilation, and mRNA and protein levels of angiogenesis-related genes were increased in venous hypertension environment. These phenomena were alleviated or eliminated by ip injection of a sirolimus solution. Sirolimus inhibited proliferation, tubule formation, migration, invasion, angiogenesis-related gene transcription and translation, and phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrate proteins S6K1 and 4EBP1. Conclusions: Abnormal angiogenesis caused by VH is related to abnormal activation of the mTOR pathway, which is important in regulating local angiogenesis; sirolimus inhibited hypertension-induced excessive angiogenesis in vivo and in vitro through the mTOR signalling pathway. This study provides a basis for further mechanistic study of AVM formation and insight into sirolimus as a possible target drug for AVM management.