Modulation of angiogenesis in adult rat brain - effect of aging, stress, environmental enrichment and antidepressant treatment

Abstract: Neurogenesis and angiogenesis are stimulated by a number of antidepressant treatments, and cellular plasticity has emerged as a phenomenon with great relevance to the etiology and treatment of depression. In paper I we characterize how ECS-induced endothelial cell proliferation leads to vascularization of the adult rat hippocampus. In the molecular layer of the hippocampus a series of 10 ECS-treatments results in 30% more endothelial cells and 16% longer vessels in treated animals compared to untreated control animals. Hippocampal neurogenesis has been proposed to occur in an angiogenic niche, with neuronal progenitors clustering close to vessels and intimately associated with dividing endothelial cells. In paper two we describe an uncoupling of the angiogenic and the neurogenic proliferative responses to ECS-treatment. The robust increase in endothelial cell proliferation following ECS-treatment is ablated in animals receiving daily injections with the stress hormone cortic osterone (CORT). Despite the inhibition of the ECS-induced angiogenesis, neuronal progenitor proliferation continues unhindered. In paper III we demonstrate increased endothelial cell proliferation in the hippocampus of animals that were exposed to environmental enrichment. The same effect was found in animals with access to running wheels. An increased endothelial cell proliferation is furthermore described in the prefrontal cortex of enriched animals, whereas running had no effect in this brain region. CORT-treated animals on the contrary displayed a 90% reduction in the number of newborn endothelial cells in both the hippocampus and the prefrontal cortex. Age is a strong negative regulator of both neurogenesis and angiogenes, and newborn cells are scarce in the hippocampus of aged animals. Despite their well established neurogenic effect, an inability of antidepressant drugs to stimulate neurogenesis in aged animals has been reported. In the fourth paper we examine the cap acity of ECS-treatment to stimulate cellular proliferation in aged rats. Glial cells proliferate abundantly in both aged and adult animals. ECS-treatment stimulates both neurogenesis and angiogenesis, but the responses are much reduced in old animals compared to younger animals. The ECS-induced angiogenesis could counter the decrease in hippocampal volume found in depressed patients, while long term exposure to CORT could lead to vascular regression, exacerbating hippocampal atrophy. Hypothetically, increased vasularization could improve hippocampal function and thereby contribute to an antidepressant effect.