The neural tube patterns vessels developmentally using the VEGF signaling pathway

Abstract

Embryonic blood vessels form in a reproducible pattern that interfaces with other embryonic structures and tissues, but the sources and identities of signals that pattern vessels are not well characterized. We hypothesized that the neural tube provides vascular patterning signal(s) that direct formation of the perineural vascular plexus (PNVP) that encompasses the neural tube at mid-gestation. Both surgically placed ectopic neural tubes and ectopic neural tubes engineered genetically were able to recruit a vascular plexus, showing that the neural tube is the source of a vascular patterning signal. In mouse-quail chimeras with the graft separated from the neural tube by a buffer of host cells, graft-derived vascular cells contributed to the PNVP,indicating that the neural tube signal(s) can act at a distance. Murine neural tube vascular endothelial growth factor A (VEGFA) expression was temporally and spatially correlated with PNVP formation, suggesting it is a component of the neural tube signal. A collagen explant model was developed in which presomitic mesoderm explants formed a vascular plexus in the presence of added VEGFA. Co-cultures between presomitic mesoderm and neural tube also supported vascular plexus formation, indicating that the neural tube could replace the requirement for VEGFA. Moreover, a combination of pharmacological and genetic perturbations showed that VEGFA signaling through FLK1 is a required component of the neural tube vascular patterning signal. Thus, the neural tube is the first structure identified as a midline signaling center for embryonic vascular pattern formation in higher vertebrates, and VEGFA is a necessary component of the neural tube vascular patterning signal. These data suggest a model whereby embryonic structures with little or no capacity for angioblast generation act as a nexus for vessel patterning.

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

“…To explore the underlying cause of the increase in blood vessels in the SQS-cKO brain, we performed in situ hybridization for VEGF mRNA, the main angiogenic factor in the developing brain (33)(34)(35). Remarkably, we observed a marked increase in VEGF mRNA expression in the E12.5 and E13.5 SQS-cKO dTE and DiE, which was largely confined to VZ (Fig.…”

Neurovascular development

“…16,17 Other pro-angiogenic factors, including VEGF-A, are also expressed, and expression of VEGF-A is regulated developmentally in the neural tube. [18][19][20][21][22] Genetic ablation of VEGF-A in the developing neural tube reduced vessel density and branching, and neural tube development was also compromised. 23,24 The studies analyzing genetic perturbation of neuronal VEGF-A illustrate an important point-that many molecular signals and guidance pathways are utilized by both the developing neural system and the developing vascular system.…”

“…We developed an explant system to co-culture quail neural tubes with mouse somitic mesoderm, and found that neural-derived VEGF was required for vessel formation from somitic tissue. 20 These studies provided a model whereby neural tube-derived VEGF-A was required for the migration and patterning of angioblasts to form the PNVP around the developing neural tube.…”

Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor

“…Mesenchymal cells in the developing embryo differentiate into vascular endothelial cells, which assemble into a primitive vascular network that remodels to provide a tissuespecific vasculature in most embryonic tissues. The developing CNS is unique in that it does not contain a primary network and is initially avascular; instead, the primary network forms a perineural plexus that surrounds the neural tube, which is then vascularized by secondary sprouts emanating from the plexus (1). This secondary sprouting is in some ways analogous to the angiogenic sprouting that leads to vascularization of initially avascular tumors.…”