Three-dimensional ultrastructure of the brain pericyte-endothelial interface

Abstract

Pericytes and endothelial cells share membranous interdigitations called “peg-and-socket” interactions that facilitate their adhesion and biochemical crosstalk during vascular homeostasis. However, the morphology and distribution of these ultrastructures have remained elusive. Using a combination of 3D electron microscopy techniques, we examined peg-and-socket interactions in mouse brain capillaries. We found that pegs extending from pericytes to endothelial cells were morphologically diverse, exhibiting claw-like morphologies at the edge of the cell and bouton-shaped swellings away from the edge. Reciprocal endothelial pegs projecting into pericytes were less abundant and appeared as larger columnar protuberances. A large-scale 3D EM data set revealed enrichment of both pericyte and endothelial pegs around pericyte somata. The ratio of pericyte versus endothelial pegs was conserved among the pericytes examined, but total peg abundance was heterogeneous across cells. These data show considerable investment between pericytes and endothelial cells, and provide morphological evidence for pericyte somata as sites of enriched physical and biochemical interaction.

Brain Capillary Pericytes are Metabolic Sentinels that Control Blood Flow through KATP Channel Activity

“…The central pathway for glucose entry into the brain is via the GLUT1 transporter, which is abundantly expressed in blood brain barrier ECs 21,44 . The cell bodies and processes of pericytes that decorate the vascular wall are embedded in the basement membrane that surrounds capillary ECs, and this intimate association allows for the extension and receipt of projections known as peg-socket junctions 11 which bring the membranes of these two cell types into very close proximity and likely facilitates the formation of gap junctions 10,19,27 . Given that gap junctions permit transfer of molecules up to 1000 Da, combined with observations of cell-cell transfer of fluorescently-conjugated glucose analogues 45,46 , it is reasonable to posit that glucose (∼180 Da) taken up into the EC cytoplasm may be transferred directly to pericytes via this avenue, the rate of which will depend ultimately on the degree of coupling between these cell types.…”

Public volume electron microscopy data: An essential resource to study the brain microvasculature

“…Link to annotations (See methods to register and agree to terms of service): https://neuromancer-seung-import.appspot.com/?json_url=https://globalv1.dafapis.com/nglstate/api/v1/5073246747623424. (Ornelas et al, 2021). Link to annotations (See methods to register and agree to terms of service): https://neuromancer-seungimport.appspot.com/?json_url=https://globalv1.dafapis.com/nglstate/api/v1/6082177280245760.…”

“…When pericyte processes encountered the location of endothelial nuclei, they tended to increase their surface coverage and proximity to the nucleus (Fig. 3B, Bi) (Ornelas et al, 2021).…”

“…D. Endothelial pegs are also enriched around pericyte somata. Images adapted from(Ornelas et al, 2021). Link to annotations (See methods to register and agree to…”

The Blood–Brain Barrier, an Evolving Concept Based on Technological Advances and Cell–Cell Communications

“…Moreover, this pathway promotes pericyte and endothelial extracellular matrix formation, as well as the production of N-cadherin protein, an adherens junction protein that enhances pericyte adhesion [ 58 , 104 , 105 ]. The close interaction between ECs and BPs induces the formation of specialised junctions, called peg and socket, which allow the exchange of small molecules, such as growth factors between ECs and BPs [ 106 , 107 , 108 , 109 ].…”