RAT-BRAIN CAPILLARY THROMBOMODULIN - STRUCTURE AND FUNCTION

The anticoagulant transmembrane glycoprotein thrombomodulin (TM) is ex pressed at the luminal surface of vascular endothelial cells. Recently , we showed that TM antigen and TM mRNA are expressed in brain microve ssels in several species and that brain capillaries have the capabilit y to activate protein C. The activation of protein C in brain microcir culation was greatly impaired by major stroke risk factors in rats due to downregulation of TM, In this study, a partial sequence of TM was determined from TM mRNA from brain capillaries examined in brain capil laries of the rat, a species that provides a useful model to investiga te stroke mechanisms in relation to brain hemostasis, The predicted de duced amino acid sequences for rat TM were compared with other TM sequ ences. Particularly high homology (77-100%) among:functional domains o f the protein, i.e,, the epidermal growth factor repeats (EGFRs) 1-6 a nd the transmembrane region, was observed between mice and rats. Somew hat less degree of homology was observed for bovine and human EGFRs 1- 6, while the homology of the transmembrane region was 92-96%, All cyst eine residues were conserved among the TM sequences, and specific amin o acids previously suggested to be essential for activation of protein C by thrombin TM were highly conserved. We conclude that the highly c onserved mRNA and protein sequences may reflect a similar anticoagulan t role of TM in brain endothelial and systemic vascular endothelial ce lls across different species. (C) 1998 Elsevier Science Ltd.