Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain

Abstract

Fenestrated capillaries of the sensory circumventricular organs (CVOs), including the organum vasculosum of the lamina terminalis, the subfornical organ and the area postrema, lack completeness of the blood-brain barrier (BBB) to sense a variety of blood-derived molecules and to convey the information into other brain regions. We examine the vascular permeability of blood-derived molecules and the expression of tight-junction proteins in sensory CVOs. The present tracer assays revealed that blood-derived dextran 10 k (Dex10k) having a molecular weight (MW) of 10,000 remained in the perivascular space between the inner and outer basement membranes, but fluorescein isothiocyanate (FITC; MW: 389) and Dex3k (MW: 3000) diffused into the parenchyma. The vascular permeability of FITC was higher at central subdivisions than at distal subdivisions. Neither FITC nor Dex3k diffused beyond the dense network of glial fibrillar acidic protein (GFAP)-positive astrocytes/tanycytes. The expression of tight-junction proteins such as occludin, claudin-5 and zonula occludens-1 (ZO-1) was undetectable at the central subdivisions of the sensory CVOs but some was expressed at the distal subdivisions. Electron microscopic observation showed that capillaries were surrounded with numerous layers of astrocyte processes and dendrites. The expression of occludin and ZO-1 was also observed as puncta on GFAP-positive astrocytes/tanycytes of the sensory CVOs. Our study thus demonstrates the heterogeneity of vascular permeability and expression of tight-junction proteins and indicates that the outer basement membrane and dense astrocyte/tanycyte connection are possible alternative mechanisms for a diffusion barrier of blood-derived molecules, instead of the BBB.

Three‐plane description of astroglial populations of OVLT subdivisions in rat: Tanycyte connections to distant parts of third ventricle

“…The distribution of laminin immunopositivity was similar to the distribution of “leaky” blood–brain barrier as described by Morita et al (). The separation of the glial and vascular basal laminae and the “leaky” vessels mutually depend on each other: a minimal perivascular space is required to receive the product of extravasation—and the extravasation inhibits the fusion of basal laminae.…”

“…Pekny () found that in the perivascular astrocytes GFAP is necessary for supporting the blood–brain barrier. In the GFAP‐rich lateral part of OVLT Morita et al () found occludin, claudin, and ZO‐1 in the capillaries and astrocytes. Therefore, these astrocytes may have a role in controlling the penetration of extravasated substances into the surrounding brain tissue.…”

“…In the “middle triangular area” of OVLT and in the core of SFO similar gradual alterations are found in the vascular immunolabeling following a double staining against β‐dystroglycan and laminin (Section 4.5, for the SFO see Pócsai & Kálmán, ). The most “leaky” vessels are in the “core” of SFO (e.g., Morita et al, ) and in the middle of OVLT in its vascular subdivision (e.g., Prager‐Khoutorsky & Bourque, ).…”

Expansion of brain T cells in homeostatic conditions in lymphopenic Rag2−/− mice

“…The approach of using lymphoid cells and T cells from GFP-transgenic mice to trace the anatomical localization revealed a more extensive relationship between these cells and cells of the CNS. The abundant localization in the ME and CVOs is not unexpected, since these structures are devoid of the BBB and in contact with the circulation (Morita et al, 2015). However, the question arises if the localization in perivascular spaces and the brain parenchyma is an epiphenomenon of the adoptive transfer approach in Rag2 −/− mice or part of a naturally occurring process.…”

From sensory circumventricular organs to cerebral cortex: Neural pathways controlling thirst and hunger

“…3 Thus, studies in mice show penetration of circulating markers such as fluorescein isothiocyanate, or higher molecular weight bovine serum albumin or dextrans permeating core regions more rapidly than peripheral subdivisions of sensory CVOs. 1,3-5 Furthermore, the altered blood-brain barrier within the sensory CVOs is not uniform in nature; fenestrated capillary endothelium is found throughout the sensory CVOs, whereas capillary tight junctions are absent in core regions but plentiful in more peripheral parts of these CVOs.…”