Developmental aspects of the intracerebral microvasculature and perivascular spaces: insights into brain response to late-life diseases

Abstract

The development of the microvasculature of the human cerebral cortex offers insight into the response of the cerebral cortex to later-life brain injury. We describe the 3 basic and distinct components of the developmental anatomy of the cerebral cortical microvascular system. The first compartment is meningeal and, therefore, extracerebral. In addition to the major venous sinuses, arachnoidal arteries, and veins, the pial anastomotic capillary plexus that covers the surface of the developing and adult cerebral cortex represents the source of thepenetrating vessels that become the second component, the intracerebral extrinsic microvascular compartment. During embryogenesis, sprouting vascular elements from pial capillaries pierce the brain's external glial limiting membrane and penetrate the cortex. These vessels, which eventually differentiate into arterioles and venules, are separated from the cortical tissue by the extravascular Virchow-Robin compartment (V-RC) formed between the internal vascular and the external glial basal laminae. The V-RC remains open to the meningeal interstitial spaces and outside the blood-brain barrier (BBB) and acts asa prelymphatic drainage system for removal of substances that cannot be transported into the blood or catabolized intracellularly. The third element is the dense intracerebralintrinsic microvascular compartment. Intracerebral capillary vessels sprout from the perforating vessels, penetrate through the Virchow-Robin glial membrane, and enter the neuropil. Intracerebral capillaries lack smooth muscle and a V-RC and consist only of endothelial cells separated from the intracerebral space by a basal lamina. Their role as the physiological BBB is the exchange of oxygen, glucose, and small molecules. This developmental perspective highlights 3 principles: (a) the V-RC is intimately related to the cortical penetrating arterioles and venules and represents an inefficient protolymphatic system that lacks the anatomic and physiological constituents found in lymphatic beds elsewhere in the body; (b)the anatomic contiguity of the V-RC and the penetrating vascular compartment (arterioles and venules) implies that the pathology in 1 compartment could lead to dysfunction in the others; and (c) the anatomic localization of the immunologic BBB at the level of the penetrating venules might impose constraints on immunologically mediated transport involving the V-RC.

Figure 1

Hematoxylin and eosin-stained sections of the developing cerebral cortex of 6-week-old (A) and 7-week-old (B) human embryos. In both, a rich pial capillary plexus with nucleated red cells covers the cerebral cortex entire surface, although internal vascularization has not yet commenced. The pial capillaries are separated from the cortical tissue by the external glial limiting membrane (EGLM) that separates the brain from surrounding tissues, and by arachnoidal and pial cells and collagen fibers. The cortical development in (A) is at the marginal zone stage; in (B) it is at the primordial plexiform stage. There are more neurons and fibers in the latter. These early cortical neuronal and fibrillar elements have arrived from extra-cortical sources and are scattered through the cortex below the EGLM (arrows) and above the hypercellular matrix zone. These early cortical elements are considered to be functionally active and their organization a prerequisite for the subsequent formation of the pyramidal cell (cortical) plate, which support a dual origin for the mammalian cerebral cortex (16, 17). C-R C= an early Cajal-Retzius Cell. Scale bars: 10 μm.

Figure 2

Composite figure of electron-photomicrographs showing various aspects of the perforation of the embryonic cerebral cortex external glial limiting membrane (EGLM) by vessels from the pial capillary plexus from 12-day-old hamster embryos. The pial capillaries (*) are small, with a diameter ranging between 5 and 10 μm, and have tight junctions (small arrows) separated from the cortex EGLM by pial (arachnoidal) cells, collagen fibers and by their respective basal laminae. (A) Small arrows indicate tight junctions, which cover the cortical EGLM (vertical arrows) composed of radial glial endfeet (G) united by tight junctions. The endothelial cells of the approaching capillary show considerable membrane activity with both internal (1 arrows) and external (2 arrows) filopodia. Some have already penetrated into the neural tissue (thick arrow). F, fibroblasts; N, neurons. (B) A high-power view of endothelial cell filopodia (E), from the approaching capillary, establishing direct contacts with the cortical EGLM (G) with fusion of both vascular and glial basal laminae. The fusion of both basal laminae precedes the filopodia perforation of the cortex EGLM. (C) Low-power view of a pial capillary (*) perforating through the cortical EGLM (thick arrows) showing the establishment of the extravascular Virchow-Robin compartment (V-RC) and the penetration of a meningeal (pericyte) cell (curved arrow), a possible precursor of vascular smooth muscle. (D) Detail of the perforating pial capillary (*) showing the establishment of the V-RC (arrows) and its external glial wall (G, arrows), which appears to be an extension of the cortex EGLM. The V-RC remains open to the meningeal interstitial spaces throughout both prenatal and postnatal cortical maturation, permitting the exchange of fluid and inflammatory cells between brain and meninges. A meningeal pericyte (P), a possible precursor of vascular smooth muscle, has penetrated into the V-RC. Key: RBC, red blood cells, PC, Pial capillary, P, Pericytes, Scale bars: 5 μm.

Figure 3

(A) Composite figure of schematic camera lucida drawings from electron-photomicrographs of 12-day-old hamster embryos, showing the pial capillary plexus with one of its vessels (PC) establishing contact with the cortex external glial limiting membrane (EGLM) (upper panel), the capillary filopodia perforation (PF) and entrance into the neural tissue with fusion of vascular and glial basal laminae at the entrance site (lower left), and the penetration of a pial perforating capillary (PC) into the cortex with the formation of the perivascular Virchow-Robin compartment (V-RC) around it (lower right). Also illustrated are the penetration of a meningeal pericyte (P) and the perforating capillary growing tip (GCS), with several advancing filopodia (PF). (B) Glial fibrillary acidic protein (GFAP)-immunostained section from an adult human brain showing the V-RC, the central perforating vessel (PV) with smooth muscles cells, a few macrophages (m) and its external wall formed by stained glial endfeet processes. The GFAP-stained section shows damaged (stained) glial cells ingested by macrophages.

Figure 4

Photomicrographs, from rapid Golgi preparations of a newborn infant motor cortex, showing the composition and tridimensional organization of its intracerebral extrinsic (A) and intrinsic (B) microvascular compartments. (A) Panel illustrates the equidistance of the pial perforators, including 2 entering arterioles [A] and an exiting venule (V) and the intrinsic microvascular capillary plexus [IMVS] established between them. The perforating vessels intervascular distance ranges between 400 μm and 600 μm and remains unchanged through both the developing and the adult cerebral cortex. (B) Higher magnification of the cortex IMVS formed between contiguous perforators showing the tridimensional organization of its capillaries and the relatively small intercapillary spaces between them, where neurons reside. There is a large stellate basket cell (BC) in one of them and some pericellular baskets formed around the unstained bodies of pyramidal cells.

Figure 5

Composite figure showing the nearly identical composition and tridimensional organization of the intracerebral extrinsic and intrinsic microvascular compartments from a newborn infant (A) and an adult brain (B). (A) A rapid Golgi preparation from the motor cortex showing an entering arteriole [A] distributed through the gray matter and an exiting venule [V], as well as the rich intrinsic capillary plexus formed between them that extends throughout both gray and white matter. The horizontal terminals of Cajal-Retzius cells axons [C-R at] are also illustrated. (B) The intravascular casting of the temporal lobe from a 66-year-old man showing an entering arteriole (number 1 in the figure) that branches through the gray (GM) matter and an exiting venule (number 5 in the figure) that reaches the white matter (WM). (From Figure 29 in [42]. Reproduced with permission from Brain Research Bulletin). 2 = recurrent arteriolar branch; 3 = deep arteriolar branch coiling around the parent arteriole; 4 = arteriole of the subcortical white matter; 6 = pial vein. Considering that the adult brain is at least 3 times larger than that of the newborn, the similarities between the brain extrinsic and intrinsic microvascular compartments that remain unchanged from prenatal to adult life are striking and are undoubtedly physiologically important.