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Postnatal development of cerebrovascular structure and the neurogliovascular unit

Advanced Review

Vanessa Coelho‐Santos, Andy Y. Shih

Published Online: Oct 01 2019

DOI: 10.1002/wdev.363

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Abstract The unceasing metabolic demands of brain function are supported by an intricate three‐dimensional network of arterioles, capillaries, and venules, designed to effectively distribute blood to all neurons and to provide shelter from harmful molecules in the blood. The development and maturation of this microvasculature involves a complex interplay between endothelial cells with nearly all other brain cell types (pericytes, astrocytes, microglia, and neurons), orchestrated throughout embryogenesis and the first few weeks after birth in mice. Both the expansion and regression of vascular networks occur during the postnatal period of cerebrovascular remodeling. Pial vascular networks on the brain surface are dense at birth and are then selectively pruned during the postnatal period, with the most dramatic changes occurring in the pial venular network. This is contrasted to an expansion of subsurface capillary networks through the induction of angiogenesis. Concurrent with changes in vascular structure, the integration and cross talk of neurovascular cells lead to establishment of blood–brain barrier integrity and neurovascular coupling to ensure precise control of macromolecular passage and metabolic supply. While we still possess a limited understanding of the rules that control cerebrovascular development, we can begin to assemble a view of how this complex process evolves, as well as identify gaps in knowledge for the next steps of research. This article is categorized under: Nervous System Development > Vertebrates: Regional Development Vertebrate Organogenesis > Musculoskeletal and Vascular Nervous System Development > Vertebrates: General Principles

Neurovascular unit of the adult rodent brain. The cellular components of the vascular wall across different microvascular zones in cerebral cortex. This schematic shows cross‐sectional views of the vascular wall composition at the level of pial arterioles on the brain surface (a), and downstream penetrating arterioles (b), precapillary arterioles (c), capillaries (d), and ascending venules (e) within the brain parenchyma

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In vivo two‐photon imaging of capillary network expansion in the postnatal brain. (Upper row) Capillaries visualized through a chronic, thinned‐skull window in a P8 mouse pup. The mouse is double transgenic for Tie2‐GFP and PDGFRbeta‐tdTomato, allowing concurrently visualization of endothelial cells (green) and pericytes (red). An fluorescent dye (Alexa 680‐dextran; 2 MDa) was injected intravenously to label the blood plasma (i.v. dye). To aid in visualization, the middle panel shows only endothelial cells with pericytes, and the right panel shows only endothelial cells and the i.v. dye. Note that many capillaries are covered by pericytes, but some regions still lack pericyte coverage/contact (middle panel). Also, many capillaries have not yet lumenized, i.e., have not filled with the i.v. dye (right panel). Further, angiogenic sprouts are clearly visible in this expanding network (white arrowheads). (Middle row) The same region of cortex was reexamined 1 day later. The angiogenic sprouts have grown further and are now integrated into an existing part of the capillary network (white arrow). (Lower row) The nascent capillary branches formed over the previous 2 days are still present, and further increase in pericyte coverage (middle panel)

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Maturation of the neurogliovascular unit. The upper panels are a schematic depicting the gradual integration of different cell types and the basement membrane in brain capillaries. The lower panels show a cross‐sectional view of the capillary wall at each developmental stage. Developmental periods (embryonic and neonate) show an angiogenic sprout with extensive filopodia. This sprout connects with an existing part of the capillary network and becomes patent. Increased tight junction density, basement membrane thickness, and astrocytic end‐foot investment contributes to BBB maturation

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Evidence for intussusceptive remodeling in the developing pial vein plexus. (a) Image montages from in vivo two‐photon microscopy provide a wide‐field view of pial arteriole and venule remodeling between P4 and P6. Arteries are pseudocolored in red and veins in blue. The inset shows a region of the vein plexus that forms small holes (yellow arrows) that grow in size over a day. These regions are devoid of blood plasma because they do not label with an intravenously injected fluorescent dye that enables visualization during microscopy, consistent with an intussusceptive pillar. Images adapted from Letourneur et al. (). (b) A schematic depicting a hypothesized mechanism for venous remodeling in the developing mammalian cerebral cortex, involving intussusceptive angiogenesis and then pruning

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Postnatal remodeling of cortical vasculature in rodents: Refinement above, expansion below. Arteries are represented in red and veins in blue. At birth, the pial surface is covered by a dense plexus of veins that undergoes pruning over the initial few weeks postnatally. Pial arteriolar structure is generally unchanged, but there is regression of some anastomotic connections. Concurrently, the capillary bed undergoes massive proliferation through generation of new angiogenic sprouts. By postnatal Days 15–25, the capillary bed is almost formed and rates of endothelial proliferation decrease

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Microvasculature of the adult rodent cortex captured by in vivo imaging. (a) An image of the cerebral cortex surface captured by in vivo two‐photon microscopy through a cranial window in an adult rat. Pial arteriole networks are pseudocolored in red, and pial venular networks are in blue. Major branches of the middle cerebral artery traverse the entirety of the window (white asterisks), and smaller anastomotic connections link these major branches to create an interconnected web (white arrowheads; two examples shown). (b, left) Highly magnified view of a pial arteriole descending into the parenchyma as a penetrating arteriole (PA; red), and an ascending venule (AV; blue) emerging from cortex and draining into a pial venule in adult mouse cortex. The dense subsurface capillary network (white) is also visible in this image because the image is a projection across 700 μm of total cortical depth. (b, right) The same penetrating arteriole in the left panel is shown from a side view, revealing its descent into the cortex. A precapillary arteriole branches from the penetrating arteriole and ramifies into the capillary network

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