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. 2015 Feb;10(1):61-73.
doi: 10.1007/s11515-014-1331-y.

Neural Regulation of CNS Angiogenesis During Development

Shang Ma  1 , Zhen Huang  2
Affiliations

Neural Regulation of CNS Angiogenesis During Development

Shang Ma et al. Front Biol (Beijing). 2015 Feb.

Abstract

Vertebrates have evolved a powerful vascular system that involves close interactions between blood vessels and target tissues. Vascular biology had been mostly focused on the study of blood vessels for decades, which has generated large bodies of knowledge on vascular cell development, function and pathology. We argue that the prime time has arrived for vascular research on vessel-tissue interactions, especially target tissue regulation of vessel development. The central nervous system (CNS) requires a highly efficient vascular system for oxygen and nutrient transport as well as waste disposal. Therefore, neurovascular interaction is an excellent entry point to understanding target tissue regulation of blood vessel development. In this review, we summarize signaling pathways that transmit information from neural cells to blood vessels during development and the mechanisms by which they regulate each step of CNS angiogenesis. We also review important mechanisms of neural regulation of blood-brain barrier establishment and maturation, highlighting different functions of neural progenitor cells and pericytes. Finally, we evaluate potential contribution of malfunctioning neurovascular signaling to the development of brain vascular diseases and discuss how neurovascular interactions could be involved in brain tumor angiogenesis.

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Figures

Figure 1
Figure 1. Neural regulation of initial vessel ingression
The blue rectangles on the top and bottom represent radial glia fibers or astrocytic processes, while the circles to the right represent cell bodies of neural progenitor cells or astrocytes. The black rectangle and triangle in the middle represent endothelial stalk and tip cells, respectively. R-Cadherin from neural cells potentially stabilizes filopodia from tip cells. Low oxygen levels or other stimuli may up-regulate Vegf gene expression within neural cells. Secreted VEGF proteins (green dots) then induce endothelial Dll4 expression, which is critical for tip cell selection and stalk cell development. Other Notch ligand such as Jagged1 has opposite functions to Dll4, suggesting that a balance between Dll4 and Jagged1 may determine tip cell number. Neural progenitor cells also secrete Wnt ligands (red dots), which stimulate endothelial cell migration probably by up-regulating MMP levels. Unidentified diffusible factors (blue dots) from neural cells may bind to GPR124 on endothelial cells to regulate Cdc42-dependent cell migration (in the forebrain).
Figure 2
Figure 2. Regulation of vessel stabilization and remodeling by neural cells
The blue rectangle on the top represents neural cells while the black rectangle on the bottom represents endothelial cells. VEGF and Angiopoietin-2 (Agpt-2) from neural cells control endothelial cell survival either separately or by synergistic actions. SSeCKS in astrocytes stimulates Angiopoietin-1 (Agpt-1) production under hyperoxia, and Agpt-1 enhances interactions between endothelial cells and the extracellular matrix (ECM). Our data suggest that unknown pathways from radial glia stabilize nascent blood vessels by suppressing endothelial Wnt signaling during later embryonic cortical development. In contrast, evidence from the retina suggests that Notch signaling pathway positively regulates Wnt signaling by Nrarp in endothelial cells and that Wnt signaling is essential for vessel stability. Latent TGFβ is widely expressed in the brain, and neural progenitor cells can localize latent TGFβ activation via integrin αvβ8 so that active TGFβ is released locally (within the vicinity of progenitor cells) to regulate blood vessel stabilization.
Figure 3
Figure 3. Regulation of blood-brain barrier (BBB) establishment and maturation by neural signals
Neural progenitor cells secrete Wnt and Sonic hedgehog (Shh) ligands that activate formation of tight junctions and expression of BBB specific transporters (such as Glut1) within endothelial cells. Pericytes are important for maintaining endothelial tight junction and other BBB properties, but unlikely to be responsible for inducing BBB. Perictye-endothelial cell interaction is mediated by N-Cadherin, which is positively regulated by TGFβ/BMP/Smad4 signaling within endothelial cells.
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