Endothelial cells lining transjugular intrahepatic portasystemic shunts originate in hepatic sinusoids: Implications for pseudointimal hyperplasia

The phenotype of the endothelial cells (ECs) in the pseudointima of transju gular intrahepatic portasystemic shunts (TIPS) and the mechanisms of pseudo intima formation after TIPS were unknown. We hypothesized that TIPS were li ned by hepatic sinusoidal ECs, which stimulated the migration of smooth mus cle cells (SMCs) into the pseudointima and their proliferation. Studies wer e done with the following specific aims: (1) isolation of ECs from TIPS pse udointima and comparison of their phenotype with human cirrhotic sinusoidal and vascular ECs derived from hepatic and portal veins as well as aorta, a nd (2) testing of the effects of TIPS ECs on TIPS-derived SMC migration and proliferation. ECs were isolated from eight TIPS retrieved from liver expl ants by immunomagnetic separation using monodispersed magnetizable polystyr ene beads (Dyna-beads M-450) coated with Ulex Europeus 1, EC phenotypes wer e examined by transmission electron microscopy, factor VIII-related antigen , CD31, CD14, and CD34 expression, uptake of acetylated LDL and secretion o f type IV collagen. The effects of EC-conditioned media on SMC migration an d proliferation were tested in multiwell chemotaxis chambers and by cell co unting, respectively. ECs were obtained from TIPS pseudointima with >95% pu rity. The phenotype of TIPS-derived ECs matched that of cirrhotic sinusoida l endothelium (both expressed CD14) and differed from that of vascular endo thelium (CD14 negative, Weibel-Palade positive). Conditioned media from bot h stenosed (n = 3) and nonstenosed (n = 3) TIPS-derived endothelial cells p roduced a marked (>100%) P < .001 increase in migration as well as (up to 8 8%) P < .01 proliferation of SMCs from both stenosed (n = 3) as well as non stenosed TIPS (n = 3), These data indicate that TIPS pseudointima are lined by hepatic sinusoidal endothelial cells, which stimulate pseudointima form ation by increasing SMC migration and proliferation.