Conditional Hypovascularization and Hypoxia in Islets Do Not Overtly Influence Adult β-Cell Mass or Function

Abstract

It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal β-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) β-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by β-cells in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult β-cell fate and metabolism. Secretion of sFlt1 by adult β-cells resulted in a rapid regression of blood vessels and hypoxia within the islets. Besides blunted insulin release, β-cells displayed a remarkable capacity for coping with these presumed unfavorable conditions: even after prolonged periods of blood vessel ablation, basal and stimulated blood glucose levels were only slightly increased, while β-cell proliferation and mass remained unaffected. Moreover, ablation of blood vessels did not prevent β-cell generation after severe pancreas injury by partial pancreatic duct ligation or partial pancreatectomy. Our data thus argue against a major role of blood vessels to preserve adult β-cell generation and function, restricting their importance to facilitating rapid and adequate insulin delivery.

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

“…The NGF expression pattern also implies that signals derived from large diameter blood vessels juxtaposed to islets and/or intra-islet pericytes should be sufficient to support adult islet function. Consistent with this notion, regression of intra-islet endothelial cells due to loss of VEGF signaling did not perturb adult insulin secretion, and elicited only modest elevations in blood glucose (D'Hoker et al, 2013; Reinert et al, 2013). In particular, impaired GSIS in isolated islets ex vivo from tamoxifen-injected Myh11-CreER T2 ;NGF f/f mice highlights an essential role for NGF produced by intra-islet pericytes in β-cell function.…”

Long-Term Function of Islets Encapsulated in a Redesigned Alginate Microcapsule Construct in Omentum Pouches of Immune-Competent Diabetic Rats

“…It is well known that the omentum is a highly vascularized tissue with endogenous angiogenic factors [41], and it appears that the ambient vascularity of the omentum provides adequate supply of nutrients and oxygen to the islet transplants. The lack of effect of enhanced neovascularization on islet graft function observed in this study is consistent with recent reports which indicate that islet vascularization is necessary in developing but not adult pancreatic islets in which the primary role of blood vessels has been suggested to be facilitating rapid and adequate delivery of insulin [44–46]. It is noteworthy that there is abundant omental tissue to accommodate high transplant volumes of encapsulated islets in large animal and human studies.…”

Human β-cell regeneration

“…Capillaries dilate in response to insulin resistance, which may increase islet function, but new angiogenesis was not seen during islet compensation [37]. Most surprising, reduction in islet vascularization, by inhibition or genetic ablation of VEGF, had no impact on β-cell mass or even function [38 ▪ ,39 ▪ ]. On the contrary, neural tissue may promote β-cell growth; co-culture with neural crest cells increased β-cell proliferation [40], and the neurotransmitter gamma-Aminobutyric acid was shown to increase human β-cell proliferation, survival, and function [41].…”