Fig. 2

Calpain systems disturb EC adaptation to the inflammatory environment. a Conventional calpains can accelerate angiogenic responses in ECs. While conventional calpains externalized by ECs exert processing of extracellular matrix thereby accelerating regenerative angiogenesis, those in ECs can potentiate pathological angiogenesis, such as tumor angiogenesis and retinopathy. Mechanistically, calpain-induced proteolysis of SOCS3 accelerates cytokine-driven production of VEGF-C. VEGF-C can synergize with VEGF-A; thus, angiogenic responses in ECs can be excessive in the presence of redundant cytokine stimuli. Furthermore, conventional calpains in cancer cells degrade VASH1, an angiogenesis inhibitor, and potentiate the production of VEGF-A. Accordingly, calpains in cancer cells positively regulate tumor angiogenesis. b Conventional calpains can proteolyze the juxtamembrane domain of VE-cadherin, leading to the disorganization of adherence junctions in ECs. Furthermore, tight junction-associated protein ZO-1 can be degraded by calpain. As a result, overactivation of conventional calpains can disrupt junctional integrity in ECs. Concomitantly, calpain proteolyzes intracellular negative regulators of inflammatory signaling, such as IκB and SOCS3, in the cells. This amplifies cytokine responses in ECs, when the cells are subjected to the additional inflammatory stimuli. CAST: calpastatin; EC: endothelial cell; ICAM-1: intercellular adhesion molecule-1; IL-6: interleukin-6; IL-6R: interleukin-6 receptor; IκB: inhibitor κB; JAK: Janus kinase; LPS: lipopolysaccaride; NF-κB: nuclear factor-κB; STAT3: signal transducer and activator of transcription 3; SOCS3: suppressor of cytokine signaling 3; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor-α; TNFR: tumor necrosis factor receptor; VASH1: vasohibin-1; VCAM-1: vascular cell adhesion molecule-1; VE-cadherin: vascular endothelial-cadherin; VEGF: vascular endothelial growth factor; ZO-1; zonula occludens-1