title: Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue.
abstract: Transplanted pancreatic islets attain a chronically decreased vascular density following transplantation, despite the increased concentrations of vascular endothelial growth factor (VEGF) secreted from beta-cells in response to hypoxia during culture and in the immediate posttransplantation phase. VEGF, however, exerts dual effects on endothelial cells, and in islet endothelial cells of the adult, the vascular permeability-inducing effects of VEGF seem normally more pronounced than those to induce angiogenesis. p38 MAP kinase activity has recently been shown to serve as a switch to separate these properties of VEGF; inhibition of p38 MAP kinase activity enhances VEGF-induced angiogenesis and, at the same time, abrogates VEGF-induced vascular permeability. We hypothesized that the revascularization of transplanted islets may be hampered by a predisposition of adult islet endothelial cells to react to VEGF by forming fenestrae rather than migrating and proliferating. We therefore administered the p38 MAP kinase inhibitor SB203580 by daily IP injections for the first 14 days following transplantation, and then studied the influence of this treatment on the oxygen tension, blood perfusion, and vascular density of the islet grafts 1 month posttransplantation. SB203580 treatment redistributed islet graft blood vessels from the stroma into the endocrine tissue, and this redistribution of blood vessels into the endocrine tissue was accompanied by an increased oxygenation of the islet cells. However, the total number of blood vessels in the tissue was not affected. The blood perfusion of the islet grafts was also similar in control and SB203580-treated animals. Our results suggest that effects of VEGF to preferentially induce vascular permeability may partially contribute to, but is not the main cause of, low revascularization of transplanted islets.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Johansson
authors.forename: Daniel
authors.initials: D
authors.lastname: Sandvik
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Carlsson
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007515:Islets of Langerhans / Q000098:blood supply; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D010100:Oxygen / Q000502:physiology; D010313:Partial Pressure; D011725:Pyridines / Q000494:pharmacology; D017154:Stromal Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D010100:Oxygen