Neurovascular development: The beginning of a beautiful friendship

Abstract

Neurovascular development in the central nervous system has a rich history and compelling significance. The developing central nervous system (CNS) does not produce vascular progenitor cells, and so ingression of blood vessels is required for continued CNS development and function. Classic studies provide elegant descriptions of formation of the vascular plexus that surrounds the embryonic brain and spinal cord, and the subsequent ingression of blood vessels into the neural tissue. Recent work has focused on the molecular pathways responsible for neurovascular cross-talk and development of the blood-brain barrier. Here we review neurovascular development in the central nervous system, with emphasis on the spinal cord. We discuss the historical work, the current status of our knowledge and unanswered questions. The importance of neurovascular development to diseases of the cerebral vasculature and the neural stem cell niche are discussed.

Figure 1

Expression of molecules involved in neurovascular cross-talk. (A) Diagram of the neurovascular unit and some of the molecular interactions between the different cell types. Endothelial cells (blue), pericytes (red), neurons (green) and glia (purple) each secrete ligands and express receptors relevant to neurovascular cross-talk and development of the blood-brain barrier. (B) Expression of relevant molecules in the developing avian neural tube at day 4.5–5 (HH stage 26) of development, when blood vessels ingress into the neural tube. Major areas of expression are noted in purple. Note the shading throughout the neural tube for VEGF-A expression to denote low VEGF-A expression in all sites. Final panel shows the vessel ingression pattern at the same stage. Information from references cited in the text.

Figure 2

Gain and loss of function of neural tube VEGF-A signaling perturbs vessel ingression patterns. Neural tubes of day 3 quail embryos were electroporated in ovo with DNA constructs expressing (A) human VEGF165 or (B) murine sFlt-1. Each cDNA was linked to eGFP via an IRES sequence, so areas of eGFP expression (green) correspond to expression of the cDNA. Embryos were processed at day 5, and sections were stained with QH1(red) to visualize blood vessels. (A) The VEGF165 electroporated (left) side of the neural tube exhibits ectopic vessel ingression points, denoted by arrows. The contralateral side does not express ectopic VEGF165 and shows the normal vessel ingression pattern (arrowheads). (B) The sFlt-1 electroporated (left) side of the neural tube exhibits loss of vessel ingression points, compared to the unmanipulated contralateral side that has a normal vessel ingression pattern (arrowheads).