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Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2006 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 15, no 6, 483-488 p.Article in journal (Refereed) Published
Abstract [en]

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 I 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.

Place, publisher, year, edition, pages
2006. Vol. 15, no 6, 483-488 p.
Keyword [en]
engraftment, Bandeiraea simplicifolia, blood flow, oxygen tension
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-24727DOI: 10.3727/000000006783981729ISI: 000241571900005PubMedID: 17121159OAI: oai:DiVA.org:uu-24727DiVA: diva2:52501
Available from: 2007-02-07 Created: 2007-02-07 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans
Open this publication in new window or tab >>Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 492
Keyword
islet transplantation, endothelial cells, engraftment, beta cells
National Category
Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-109713 (URN)978-91-554-7643-4 (ISBN)
Public defence
2009-12-05, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2009-11-13 Created: 2009-10-22 Last updated: 2009-11-13

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Johansson, ÅsaCarlsson, Per-Ola

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