Summary. Background: Endothelial cell protein C receptor (EPCR) binds protein C through its c-carboxyglutamic acid (Gla) domain and enhances its thrombin-thrombomodulin complex-dependent activation. So far, only protein C/ activated protein C has been shown to interact with EPCR. Factor VII (FVII), the coagulation trigger upon tissue factor (TF) interaction, is a serine protease whose Gla domain is highly homologous to the Gla domain of protein C. Objectives: To characterize the binding of FVII/FVIIa to EPCR and its functional consequences. Methods and results:We demonstrated by surface plasmon resonance (SPR) that FVII/FVIIa binds to EPCR through its Gla domain. At therapeutic concentrations, FVIIa reduced the activation of protein C by 40%. Soluble EPCR (sEPCR) was also able to prolong dose-dependently the clotting time induced by the FVIIa-TF complex. SPR and amidolytic experiments showed that FVIIa is able to interact simultaneously with TF and EPCR, thus ruling out the possibility that the effect of EPCR on clotting time was due to the inhibition of the binding between FVIIa and TF. sEPCR inhibited dose-dependently the activation of FX by the FVIIa-TF complex. Notably, blocking the binding site of EPCR on the endothelial surface increased the generation of FXa 2-fold. Conclusions: EPCR binds to FVII/ FVIIa and inhibits the procoagulant activity of the FVIIa-TF complex.

The pathogenesis of hypogonadism in cirrhosis is not completely understood. The levels of insulin-like growth factor-I (IGF-I), an anabolic factor with trophic actions on testes, are reduced in cirrhosis. This study was undertaken to evaluate whether rats with advanced cirrhosis develop hypogonadism and whether the administration of IGF-I exerts beneficial effects on testicular structure and function. Wistar rats with ascitic cirrhosis induced with CCl 4 were allocated into 2 groups (n ‫؍‬ 10, each) to receive recombinant IGF-I (20 g · kg ؊1 · d ؊1 , subcutaneously) or vehicle for 3 weeks. Healthy rats receiving vehicle were used as the control group (n ‫؍‬ 10). At baseline, both cirrhotic groups showed similar deterioration of liver function tests. Compared with controls, nontreated cirrhotic rats showed decreased serum levels of IGF-I (P F .05), reduced testicular size and weight (P F .001), and intense histopathological testicular abnormalities, including reduced tubular diameters (P F .001), loss of the germinal line (P F .001), and diminutions in cellular proliferation, spermatogenesis (P F .001), and testicular transferrin expression (P F .001). In addition, low serum testosterone (P F .01) and high serum LH (P F .01) were present in untreated cirrhotic animals. Cirrhotic rats that received IGF-I showed full recovery of testicular size and weight and of all histopathological abnormalities (P F .001 to F .01 vs. nontreated cirrhotic rats; P ‫؍‬ ns vs. controls). Serum levels of sex hormones tended to normalize. In conclusion, IGF-I deficiency may play a pathogenetic role in hypogonadism of cirrhosis. Low doses of IGF-I for a short period of time revert testicular atrophy and appear to improve hypogonadism in advanced experimental cirrhosis. (HEPATOLOGY 2000;31:592-600.)Hypogonadism is a frequent complication of advanced cirrhosis. This condition is characterized by low testosterone levels and relative hyperestrogenism and is frequently associated with loss of libido, sexual impotence and feminine body habitus in men and amenorrhea in women.

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MMP-10 is involved in the development of microvascular complications in type 1 diabetes and emerges as a potential therapeutic target for slowing down the evolution of diabetic nephropathy and retinopathy.

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