Changes in islet microvasculature following streptozotocin-induced β -cell loss and subsequent replacement in the neonatal rat

Abstract

Neonatal rats undergo considerable β-cell regeneration after depletion with streptozotocin (STZ). Since the intraislet vasculature is necessary for both β-cell growth and function, we examined changes in vascular morphology following STZ. Neonatal Wistar rats (4 days) were injected with 70 mg/kg STZ, or buffer, and were examined between days 4 and 40 postinjection. Animals receiving STZ were relatively hyperglycemic for eight days, but became normoglycemic subsequent to a partial recovery of β-cell mass. However, glucose tolerance remained impaired. The intraislet area occupied by capillaries was significantly reduced by approximately 20% following STZ, mainly within the β-cell-rich islet core, but had recovered by day 40. Vascular endothelial growth factor (VEGF) was localized to β-cells, and pancreatic VEGF mRNA levels in control animals showed a progressive increase between days 4 and 20. This rise was delayed following STZ, but by day 20 VEGF mRNA abundance exceeded that in control pancreas. Hepatocyte growth factor (HGF) was localized to intraislet endothelial cells. Levels of HGF mRNA increased until day 16 in control rats, but subsequently declined to low levels. Following STZ, HGF mRNA had declined prematurely after day 12. Type IV collagen was localized to the extracellular matrix around the intraislet vasculature. The islet area immunopositive for collagen was significantly reduced at all times following STZ. Results indicate that there is a relative loss of intraislet vasculature following STZ, which may limit subsequent β-cell regeneration through both local growth factor and extracellular matrix interactions.