Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression.

Recent evidence has shown that cell proliferation in the adult hippocampal dentate gyrus occurs in tight clusters located near the vasculature. Also, changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptor Flk-1. In an earlier study we found that chronic stress decreased new cell proliferation in the adult dentate gyrus. We here questioned whether these effects of chronic stress are mediated through the vasculature and whether they involve an angiogenic-signaling pathway. We therefore measured the surface area covered by the vasculature, the proportion of vascular-associated newborn cells, and analysed VEGF and Flk-1 protein expression in the hippocampus of a control, chronically stressed and recovery group of rats. Our results show that 32% of the proliferating cells in the rat hippocampus is vascular associated. Chronic stress affected this population of newborn cells to a significantly larger extent than the non-associated cells. Interestingly, after 3 weeks of recovery, the decreased proliferation not associated with the vasculature was more effectively restored than vascular-associated proportion of proliferating cells. VEGF protein was expressed in high densities in GFAP-positive astrocytes located in the hilus, with VEGF-positive end feet extending into and often contacting the granule cells. After chronic stress, both VEGF and Flk-1 protein levels were significantly decreased in the granular cell layer, and again recovered after 3 weeks. This demonstrates that changes in angiogenic factors are implicated in the decreased adult proliferation found after chronic stress.