‘Sealing off the CNS’: cellular and molecular regulation of blood–brain barriergenesis
Section snippets
Cellular regulation of barriergenesis: pericytes
Pericytes are an important perivascular cell type related to vascular smooth muscle cells (vSMCs) and are largely defined by their location with the vascular plexus (small-diameter capillaries) and close interaction with endothelial cells [10]. Pericytes are found at high density in CNS vasculature and their important role in neurovascular development is underscored by mouse models of pericyte-deficiency caused by genetic disruption of platelet-derived growth factor-B (PDGFB) signaling [11, 12•
Cellular regulation of barriergenesis: astrocytes
In the latter half of gestation in human development [22] and soon after birth in mice [3••], astrocytic processes or endfeet ensheath the brain endothelium and, in this position, they are poised to aid in the maturation and maintenance of the BBB. Evidence of a role for astrocytes in barrier maturation is based on several in vitro studies showing that either co-culture with astrocytes or astrocyte-conditioned media induces BBB properties in cultured endothelial cells, specifically increased
Molecular regulation of barriergenesis
Although it is clear that pericytes and astrocytes can regualte barrier properties during development and adulthood, many important BBB-specific properties appear to be under control of embryonic neural progenitors. The appearance of specialized TJs and the expression of transporters are important events in barriegenesis that arise in the absence of pericytes and before astrocyte generation, and likely depend on neural progenitor-derived signals. Indeed, in vitro cell culture experiments have
Concluding remarks
The complexity of signals involved in blood brain barriergenesis not only reflects the different properties of the BBB but also the temporal acquisition of these properties during prenatal and postnatal brain development. Expression of different transporters, accumulation of TJ structures and proteins and decline in LAMs are not instantaneous events as blood vessels enter neural tissue. The induction of these properties appears to be orchestrated by a series of different cellular interactions
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (47)
- et al.
Early ultrastructural changes in blood–brain barrier vessels of the rat embryo
Brain Res Dev Brain Res
(1994) - et al.
Neovascularization and the appearance of morphological characteristics of the blood–brain barrier in the embryonic mouse central nervous system
Brain Res Dev Brain Res
(1993) - et al.
Efflux mechanisms at the developing brain barriers: ABC-transporters in the fetal and postnatal rat
Toxicol Lett
(2010) - et al.
Pericytes: developmental, physiological, and pathological perspectives, problems, and promises
Dev Cell
(2011) - et al.
Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities
Development
(2004) - et al.
Pericytes regulate the blood–brain barrier
Nature
(2010) - et al.
Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging
Neuron
(2010) - et al.
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Nature
(2012) - et al.
Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis
J Neurosci
(2007) - et al.
Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells
J Neurochem
(2008)
Death receptors DR6 and TROY regulate brain vascular development
Dev Cell
A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse
Mech Dev
Pericytes are required for blood–brain barrier integrity during embryogenesis
Nature
Observations of vascularization in the spinal cord of mouse embryos, with special reference to development of boundary membranes and perivascular spaces
Anat Rec
Development of the blood–brain barrier to horseradish peroxidase in the chick embryo
Cell Tissue Res
Brain induces the expression of an early cell surface marker for blood–brain barrier-specific endothelium
EMBO J
Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study
J Physiol
Development of blood–brain barrier tight junctions in the rat cortex
Brain Res Dev Brain Res
Pericyte loss and microaneurysm formation in PDGF-B-deficient mice
Science
Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse
Development
Pericytes augment the capillary barrier in in vitro cocultures
J Surg Res
Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-beta production
Brain Res
Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders
Nat Rev Neurosci
Cited by (85)
Neurovascular dysfunction in glaucoma
2023, Progress in Retinal and Eye ResearchThe role of angiotensin peptides in the brain during health and disease
2023, Angiotensin: From the Kidney to CoronavirusForm follows function: The endothelial glycocalyx
2022, Translational ResearchThe blood-brain barrier in health, neurological diseases, and COVID-19
2022, Fundamental ResearchCitation Excerpt :The BBB is surrounded by or closely associated with other cell types in the NVUs, including neurons, microglia, and, optionally, blood-borne immune cell populations that also contribute to the modulation of BBB functions [4]. BBB formation in mammals initiates at the early embryonic period when endothelial progenitor cells enter the cortex and vascularize the CNS [5]. The exact timing is species-dependent and varies regionally.
Neurosurgery at the crossroads of immunology and nanotechnology. New reality in the COVID-19 pandemic
2022, Advanced Drug Delivery Reviews