Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway.

Abstract

Appropriate formation of blood vessels is critical for tendon-bone healing during tendon injury, as excessive angiogenesis would exacerbate scar formation and lead to chronic pain and dysfunction. The mechanism to regulate inflammatory angiogenesis during tendon-bone healing remains to be elucidated. Here, we utilized lipopolysaccharide (LPS) to induce tenocyte inflammation and applied the conditioned medium from inflammatory tenocytes to treat rat aortic vascular endothelial cells (RAOECs). The results that indicated LPS treatment significantly induced the mRNA and protein upregulation of NLRP3, tumor necrosis factor α, IL-1β, and vascular endothelial growth factor A (VEGFA), as well as the secretion of VEGFA. Furthermore, the conditioned medium stimulated RAOEC angiogenesis. Celastrol, a quinone-methylated triterpenoid from Tripterygium wilfordii, has been reported to treat osteoarthritis. Here, celastrol could suppress LPS-induced upregulation of NLRP3 and IL-1β, and the secretion of VEGFA. Celastrol treatment also suppressed the conditioned medium-induced angiogenesis in RAOEC. Moreover, we established a rotator cuff tear rat model to stimulate tendon injury. Celastrol administration at the lesion significantly promoted tendon healing and functional recovery in injured mice by regulating NLRP3 and VEGFA levels. Taken together, these data suggest that the inflammation-induced tenocyte injury leads to angiogenesis, and that celastrol administration could suppress the inflammatory tenocyte-induced angiogenesis to promote tendon-bone healing via the NLRP3 pathway.