Development and Function of the Blood-Brain Barrier in the Context of Metabolic Control

Abstract

Under physiological conditions, the brain consumes over 20% of the whole body energy supply. The blood-brain barrier (BBB) allows dynamic interactions between blood capillaries and the neuronal network in order to provide an adequate control of molecules that are transported in and out of the brain. Alterations in the BBB structure and function affecting brain accessibility to nutrients and exit of toxins are found in a number of diseases, which in turn may disturb brain function and nutrient signaling. In this review we explore the major advances obtained in the understanding of the BBB development and how its structure impacts on function. Furthermore, we focus on the particularities of the barrier permeability in the hypothalamus, its role in metabolic control and the potential impact of hypothalamic BBB abnormities in metabolic related diseases.

Keywords: blood-brain barrier; development; hypothalamus; inflammation; neurovascular unit; obesity.

Figure 1

Neurovascular unit (NVU). A layer of brain endothelial cells connected by tight junctions forms the blood-brain barrier. The intimate contact of these specialized endothelial cells with different cell types constitutes the NVU. A basement membrane embeds the brain endothelial cells, the pericytes, and astrocytes. In areas where the basement membrane is absent, brain endothelial cells and pericytes connect through peg-socket junctions. Astrocytes extend its end-feet and establish a close interaction with endothelial cells through transmembrane proteins, such as aquaporins. Astrocytes also connect with pericytes and neurons and together regulate BBB maintenance and function. The interaction of the cell components of the NVU with neurons and microglia can influence barrier function.

Figure 2

BBB development and maintenance. (A) Angiogenesis and differentiation. VEGF secretion from neural progenitor cells induces endothelial cells penetration into the brain parenchyma according to a VEGF concentration gradient. Wnt ligands also secreted from the NPCs induces the migration of the endothelial cells and activate β-catenin signaling through the binding to Frizzled receptors, inducing the expression of BBB specific genes. GPR124, together with WNT, co-activates β-catenin signaling. Endothelial cells secrete PDGF-B and attract pericytes expressing PDGFR-β. The interaction between ECs and Ps induce the mutual expression of TGF-β and TGF-βR2. The activation of TGF-β signaling regulates basement membrane formation and the induction of Ang-1 expression in pericytes, that acting through the endothelial receptor Tie-2, enhance tight junction expression. Astrocytes release SHH, that when bound to PTCH receptor induces Shh signaling activation in ECs and contributes to BBB formation. Astrocytes also express ANT and ANG-1, which by limiting BBB permeability contributes to the maturation of BBB function. (B) Maturation and Maintenance. Pericytes and astrocytic end-feet cover the endothelium and secrete matrix proteins that will constitute the basement membrane. Astrocytes continue secreting SHH and WNT in order to maintain BBB functionality throughout life. A, astrocytes; E, endothelium; EC, endothelial cell; M, microglia; N, neuron; NPC, neural progenitor cell; P, pericyte; TJ, tight junction; Ang-1, angiopoietin-1; ANT, angiotensin; β-cat, beta-catenin; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; FZD, frizzled; GPR124, adhesion G protein coupled receptor A2; Shh, sonic hedgehog; Ptch, Patched 1; PDGF-B, platelet derived growth factor B; PDGFR-β, platelet derived growth factor receptor beta; TGF-β, transforming growth factor-beta; TGF-βR2, transforming growth factor beta receptor type-2.

Figure 3

Organization of the BBB in the energy-sensing hypothalamus. (A) Coronal section of the tuberal hypothalamus showing the distribution of tanycytes along the third ventricle wall. Left: vimentin staining (red) shows the projections of tanycytes to the brain parenchyma. Right: tanycytes line the third ventricle and can be classified according to location and function. α tanycytes don't possess barrier properties. α1 tanycytes (dark red) lye in the dorsal ventro-medial nucleus of the hypothalamus, while α2 tanycytes (light red) are found in between the ARC and the VMH. β tanycytes are located ventrally and function as gatekeeper cells controlling the passage of substances from the leaky ME to the ARC. β1 tanycytes (turquose) divide the ME from the ARC, while β2 tanycytes (green) are located in the ME, and characterized by processes with direct access to the blood capillaries. Blood capillaries are displayed in light pink. (B) Diagram showing how the diffusion of dyes injected peripherally do not penetrate the brain (exemplified here by the action of tanycytes lining the ME and the ARC) (left). On the other hand, dyes that are infused inside of the brain ventricles diffuse trhough the CSF and penetrate the brain parenchyma but do not pass the ME in the direction of the portal capillaries (right). VMN, ventro-medial nucleus; ARC, arcuate nucleus; ME, median eminence; 3V, third ventricle.