InflammatoryCaspase‐1 Activation and Vegfr‐2 Signaling Regulate Each Other in Lipid Stimulated Endothelial Cells

Abstract

BackgroundVascular inflammation is reported to be an antiangiogenic state, however, the underlying mechanism remains unknown. More specifically, the interplays between danger‐associated molecular pattern (DAMP) sensing in endothelial cell (EC), EC activation and EC growth are poorly defined. We tested a novel hypothesis that the caspase‐1 activation and VEGFR‐2 pathway regulate each other in inflammatory lipid stimulated EC.Methods and ResultsWe assayed caspase‐1 activity in human aortic endothelial cells (HAECs) stimulated with lysophosphatidylcholine (LPC). Using flow cytometry we analyzed the EC size, death, caspase‐1 activation and VEGFR‐2 pathway in LPC stimulated EC. We made the following findings: LPC increases caspase‐1 activity in larger size EC first that is associated with EC activation; and then in smaller size EC, which is associated with inflammatory cell death as judged by 7‐AAD staining. LPC decreases VEGFR‐2 expression in EC, whereas the inhibition of caspase‐1 increases the expression of VEGFR‐2 after LPC treatment in EC, which leads to an improvement in tube formation. The caspase‐1 deficient mice have an increase in the blood flow after hind limb ischemia presumably via enhancing angiogenesis.ConclusionOur results indicate for the first time that caspase‐1 inhibition increases VEGFR‐2 signaling pathway after lipid stimuli in EC. The interplays of inflammatory caspase‐1activation and VEGFR‐2 signaling pathway could be a novel therapeutic target for vascular inflammation and angiogenesis.