Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for β-Cell Function

Abstract

OBJECTIVELoss of thrombospondin (TSP)-1 in pancreatic islets has been shown to cause islet hyperplasia. This study tested the hypothesis that endothelial-derived TSP-1 is important for β-cell function.RESEARCH DESIGN AND METHODSIslet function was evaluated both in vivo and in vitro. Messenger RNA and protein expression were measured by real-time PCR and Western blot, respectively. The role of endothelial-derived TSP-1 for β-cell function was determined using a transplantation design in which recipient blood vessels either were allowed to grow or not into the transplanted islets.RESULTSTSP-1–deficient mice were glucose intolerant, despite having an increased β-cell mass. Moreover, their islets had decreased glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate, as well as increased expression of uncoupling protein-2 and lactate dehydrogenase-A when compared with control islets. Almost all TSP-1 in normal islets were found to be derived from the endothelium. Transplantation of free and encapsulated neonatal wild-type and TSP-1–deficient islets was performed in order to selectively reconstitute with TSP-1–positive or –negative blood vessels in the islets and supported that the β-cell defects occurring in TSP-1–deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells. Treatment of neonatal TSP-1–deficient mice with the transforming growth factor (TGF)β-1–activating sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented the development of decreased glucose tolerance in these mice. Thus, endothelial-derived TSP-1 activates islet TGFβ-1 of importance for β-cells.CONCLUSIONSOur study indicates a novel role for endothelial cells as functional paracrine support for pancreatic β-cells.

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

“…However, additional VEGF-A is not necessarily beneficial-while VEGF-A overexpression may increase the number of intraislet vascular ECs, the resultant vasculature is dysfunctional and islet function is impaired (14). Within islets, the abundant production of proangiogenic VEGF-A is balanced by angiostatic and antiangiogenic factors, including thrombospondin-1 (15). Thus it appears that in the steady-state, VEGF-A production is strictly controlled to maintain the intraislet vasculature at an appropriate density and with functional architecture.…”

“…In islets, thrombospondin-1 is almost exclusively expressed by the intraislet endothelium. Thromobspondin-1 is upregulated in human islets by high glucose (16), and while knockout mice have increased b-cell mass and improved revascularization of transplanted islets (17), they are glucose intolerant and display impaired islet function (15). In addition to its antiangiogenic properties, thrombospondin-1 activates latent transforming growth factor-b (a potent regulator of adult b-cell insulin gene transcription and islet function [18]).…”

Superior beta cell proliferation, function and gene expression in a subpopulation of rat islets identified by high blood perfusion

“…Vascular basement proteins such as laminins produced by the endothelial cells promote insulin gene expression and beta cell proliferation and enhance glucose-stimulated insulin release [4,5]. We also recently showed that endothelial-derived thrombospondin-1 is important for beta cell differentiation and function [6]. Moreover, hepatocyte growth factor production can be induced by vascular endothelial growth factor-A (VEGF-A) and insulin in islet endothelial cells, further contributing to beta cell proliferation during increased functional demand [7].…”

The endocrine role between β cells and intra-islet endothelial cells [Review]

“…In normal islets, TSP-1 is primarily produced by endothelial cells [29], and it can induce the islets produce TGF-β [21], which may initiate a signaling cascade leading to Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/ JNK) pathway activation [30], to establish and maintain defining features of mature pancreatic β cells [31]. Studies found that in TSP-1-deficient mice, glucose-stimulated insulin release is decreased [29], which therefore suggests the critical role of TSP-1 production of insulin.…”