Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Abstract

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.

Diverse roles for VEGF-A in the nervous system

“…2B,C). By contrast, it has been convincingly shown that the closely related factor VEGF-C signals directly to neural stem cells and niche astrocytes through its receptor VEGFR3 (FLT4) independently of its alternative roles in lymphatic or blood vessels (Calvo et al, 2011).…”

Molecular Parallels between Neural and Vascular Development

“…Vegf-c deletion in the mouse, as well as VEGF-C knockdown in Xenopus tadpoles, inhibited proliferation of neural progenitor cells in the forebrain, without defects of the brain vasculature, indicating that VEGF-C is a trophic factor for subsets of neural progenitor cells in the vertebrate embryonic brain (LeBras et al 2006). The high-affinity VEGF-C receptor VEGFR-3 is also expressed by embryonic and adult neural cells (Choi et al 2010;Calvo et al 2011). Using transgenic VEGFR-3 mice expressing a YFP reporter or conditional deletions of VEGFR-3 in neural cells, we have shown that, in the adult SVZ, VEGF-C/VEGFR-3 signaling acted in niche astrocytes and NSCs to stimulate neurogenesis (Calvo et al 2011).…”

“…VEGF-B, a VEGFR-2 ligand, has a trophic role in adult neurogenesis, as shown by impaired neurogenesis of Vegf-b-KO mice and the neurogenesis-promoting effect of VEGF-B, which is able to restore neurogenesis in Vegf-b-KO (Sun et al 2006). The lymphangiogenic factor VEGF-C is also expressed in the embryonic (LeBras et al 2006) and adult brain (Shin et al 2008;Calvo et al 2011) in rodents. Vegf-c deletion in the mouse, as well as VEGF-C knockdown in Xenopus tadpoles, inhibited proliferation of neural progenitor cells in the forebrain, without defects of the brain vasculature, indicating that VEGF-C is a trophic factor for subsets of neural progenitor cells in the vertebrate embryonic brain (LeBras et al 2006).…”

“…The high-affinity VEGF-C receptor VEGFR-3 is also expressed by embryonic and adult neural cells (Choi et al 2010;Calvo et al 2011). Using transgenic VEGFR-3 mice expressing a YFP reporter or conditional deletions of VEGFR-3 in neural cells, we have shown that, in the adult SVZ, VEGF-C/VEGFR-3 signaling acted in niche astrocytes and NSCs to stimulate neurogenesis (Calvo et al 2011). Therefore, VEGF/VEGFR family members provide complementary signals to the different cellular populations in the neurovascular niche, VEGF-C/VEGFR-3 signaling supporting resident astrocytes and stimulating NSC divisions, whereas VEGF-A/VEGFR-2 signaling maintains the niche vasculature and promotes amplification and migration of neuronal progenitors (Fig.…”

Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

“…It is also believed to act on neural stem/progenitor cells via the VEGF receptor 3 (VEGFR-3) and regulate neurogenesis in developing and adult brains (Calvo et al 2011;Le Bras et al 2006). In addition, VEGF-C/VEGFR-3 is induced in reactive astrocytes, perivascular-infiltrated macrophages, and activated microglia in rats with ischemic stroke and experimental autoimmune encephalomyelitis.…”