Vascular Endothelial Growth Factor–Mediated Islet Hypervascularization and Inflammation Contribute to Progressive Reduction of β-Cell Mass

Abstract

Type 2 diabetes (T2D) results from insulin resistance and inadequate insulin secretion. Insulin resistance initially causes compensatory islet hyperplasia that progresses to islet disorganization and altered vascularization, inflammation, and, finally, decreased functional β-cell mass and hyperglycemia. The precise mechanism(s) underlying β-cell failure remain to be elucidated. In this study, we show that in insulin-resistant high-fat diet-fed mice, the enhanced islet vascularization and inflammation was parallel to an increased expression of vascular endothelial growth factor A (VEGF). To elucidate the role of VEGF in these processes, we have genetically engineered β-cells to overexpress VEGF (in transgenic mice or after adeno-associated viral vector-mediated gene transfer). We found that sustained increases in β-cell VEGF levels led to disorganized, hypervascularized, and fibrotic islets, progressive macrophage infiltration, and proinflammatory cytokine production, including tumor necrosis factor-α and interleukin-1β. This resulted in impaired insulin secretion, decreased β-cell mass, and hyperglycemia with age. These results indicate that sustained VEGF upregulation may participate in the initiation of a process leading to β-cell failure and further suggest that compensatory islet hyperplasia and hypervascularization may contribute to progressive inflammation and β-cell mass loss during T2D.

Short-term overexpression of VEGF-A in mouse beta cells indirectly stimulates their proliferation and protects against diabetes

“…In line with previous reports [12], extended overexpression of VEGF-A rather promotes reduction in the beta cell mass and dysglycaemia. Insulinresistant, high fat diet fed mice display increased VEGF-A levels and islet vascularisation, coinciding with islet hyperplasia [12], and obese individuals counteract increased insulin resistance by an initial expansion of the beta cell mass [24].…”

“…On the other hand, pre-or neonatal VEGF overexpression also negatively affects beta cell proliferation, resulting in reduced beta cell mass [12,13]. In our study, 2 weeks of continuous administration of BrdU to +DOX 14D mice increased the number of cycling beta cells by almost 50% (Fig.…”

“…On the other hand, gain-of-function experiments have revealed a detrimental effect of excessive VEGF levels on islet integrity and on beta cell proliferation and development when overexpressed at embryonic or neonatal stages [8,12,13]. However, no conditional gain-of-function studies have as yet evaluated the effect of VEGF on islet vascularisation and beta cell proliferation/survival in adult normoglycaemic and beta cell toxin-exposed animals, which represent a clinically more relevant situation.…”

“…Under normoglycaemic conditions, 14 days of VEGF-A overexpression by beta cells increased islet vessel density by 35%. Some have reported no changes in islet vascularisation [23] while others have shown a net increase [12] following constitutive overexpression of VEGF-A in beta cells. These differences likely relate to the time-point of analysis, extent of VEGF-A induction and method of analysis (vessel number vs vessel area per islet).…”

“…Furthermore, islet endothelial cells play a role during adult beta cell expansion under conditions of increased physiological insulin demand (pregnancy) by releasing the beta cell mitogen hepatocyte growth factor (HGF) in response to a prolactin-induced increase in the intra-islet levels of insulin and VEGF-A [11]. On the other hand, tight control of VEGF-A expression and fine-tuned delivery of VEGF-A is crucial for proper beta cell development and function [2,7] since excessive VEGF-A levels, induced prenatally or neonatally, result in endothelial cell accumulation, vascular leakage and inflammatory cell infiltration and ultimately have a deleterious effect on islet development and function [8,12,13].…”