Reversible modulations of neuronal plasticity by VEGF

Abstract

Neurons, astrocytes, and blood vessels are organized in functional “neurovascular units” in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons.

Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain

“…In line with such a role of VEGF, it was recently reported that conditional transient increase of VEGF expression for 5-15 days leads to significant increase of long-term potentiation in the hippocampus through modulation of synaptic plasticity in mature neurons [41]. In addition, VEGF has been implicated as a mediator of human NSC-induced effects on dendritic sprouting, axonal plasticity, and axonal transport [15].…”

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

“…In addition, blood circulating factors have substantial effects over the process of neurogenesis (79)(80)(81)(82). VEGF is one of these factors (83), and can stimulate neurogenesis (84)(85)(86) and reversibly modulate neuronal plasticity (87). Other blood-derived factors capable of affecting neurogenesis are glucocorticoids, which are necessary for the regulation of neuronal differentiation and migration (88).…”

VEGFR1 and VEGFR2 in Alzheimer’s Disease

“…VEGF-A (VEGF) is a pro-angiogenic factor [20,21] that is also involved in neuroprotection, neurogenesis, synaptic plasticity, and modulation of inflammation and astrocyte proliferation [22][23][24][25][26]. It is upregulated in response to hypoxia [27,28] and elevated within hypoperfused cortex and white matter in small vessel disease, vascular dementia and AD [3,[29][30][31][32].…”