ADAMTS13 biosynthesis appeared to occur mainly in hepatic stellate cells, but detection of ADAMTS13 mRNA in many other tissues suggests that vascular endothelium may also produce ADAMTS13. We showed that ADAMTS13 mRNA and protein were detectable in human umbilical vein endothelial cells, aortic endothelial cells, and endothelium-derived cell line (ECV304). ADAMTS13 in cell lysate or serum-free conditioned medium cleaved von Willebrand factor (VWF) specifically.
IntroductionADAMTS13, a member of a disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS) family, limits plateletrich thrombi by cleaving von Willebrand factor (VWF) between the Tyr 1605 and Met 1606 residues. VWF is synthesized in vascular endothelial cells and megakaryocytes or platelets, and normally stored in Weibel-Palade bodies 1 of endothelial cells or the ␣-granules of platelets. 2,3 Upon stimulation, VWF is secreted as unusually large (UL) multimers that may remain associated with the endothelial cell surface. [4][5][6] These UL-VWF multimers may be the preferred substrate for ADAMTS13. 4,5 Inability to cleave these UL-VWF multimers to smaller sizes on the endothelial cell surface may result in an accumulation of UL-VWF, leading to enhanced platelet adhesion and aggregation, and thrombotic thrombocytopenic purpura (TTP), 7,8 characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, and organ failure. 7,8 ADAMTS13 appears to be synthesized in liver, 9-11 particularly in hepatic stellate cells, [12][13][14] which reside in the space of Disse adjacent to the hepatocytes. However, the contribution of hepatic stellate cells in regulation of plasma ADAMTS13 levels remains to be determined. We have recently shown that despite a dramatic increase in ADAMTS13 expression in hepatic stellate cells upon activation by administration of carbon tetrachloride, plasma ADAMTS13 activity is not proportionally increased in rats. 14 In addition, patients with liver cirrhosis or with significant proliferation and activation of hepatic stellate cells exhibit variable or reduced levels of plasma ADAMTS13 activity. 15 Therefore, plasma ADAMTS13 protease may be derived from other sources as well.Recent reports have shown that ADAMTS13 is synthesized and released from human megakaryocytes and platelets. 16,17 ADAMTS13 mRNA is detected in almost every organ tissue by reversetranscriptase-polymerase chain reaction (RT-PCR), [9][10][11]18,19 suggesting that the vascular endothelium may also be the source of plasma ADAMTS13. Considering the enormous surface area of vascular endothelial beds, a small fraction of endothelial cells producing ADAMTS13 at any given time may contribute significantly to plasma levels of ADAMTS13 activity. Consequently, any perturbation of endothelial cell function or ADAMTS13-VWF interactions at the site of their syntheses by inflammatory cytokines or drugs may play an important role in the pathogenesis of TTP 20,21 and perhaps other thrombotic complications. 22 ADAMTS13 consists of signal peptide, propepti...
