Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans

Sammanfattning: Transplantation of insulin producing cells is currently the only cure for type 1 diabetes. However, even though the Edmonton protocol markedly increased the success rate of pancreatic islet transplantation, the long term insulin independence is still very poor. An adequate engraftment is critical for islet graft survival and function.In the present thesis, isolated islet endothelial cells were found to have a low proliferatory and migratory capacity towards vascular endothelial growth factor (VEGF), but this could be reversed by using neutralizing antibodies to the angiostatic factors thrombospondin-1, endostatin or alpha1-antitrypsin.In the adult islet endothelial cell, VEGF may act as a permeability inducer more than an inducer of angiogenesis. p38 MAP kinase activity has been shown to serve as a switch between these properties of VEGF. Inhibition of p38 MAP kinase by daily injections of SB203580 in the early posttransplantation phase lead to a redistribution of the islet graft blood vessels from the stroma into the endocrine tissue and this was accompanied by a higher oxygen tension.Besides transports of oxygen and nutrients, beta-cells may require signals from the endothelial cells for their growth and differentiation. It was demonstrated that islet endothelial cells secrete factors, including laminin, that have positive effects on beta-cell insulin release and insulin content.Our results suggest that improved revascularization of transplanted islets may be achieved by either inhibition of angiostatic factors, or by blocking p38 MAPkinase activity, in the implanted tissue. Islet endothelial cells have a supportive paracrine role for beta-cells that might be hampered by the normally poor revascularization.