The impact of pericytes on the blood–brain barrier integrity depends critically on the pericyte differentiation stage

Thanabalasundaram, Gokulan; Schneidewind, Jana; Pieper, Christian; Galla, Hans‐Joachim

doi:10.1016/j.biocel.2011.05.002

Cited by 108 publications

(81 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to TGF-β, exogenous FGF-2 and IL-6 maintained pulmonary pericytes in a noncontractile state in culture and prevented the pericyte differentiation induced by serum deprivation. Our findings are consistent with those found by Thanabalasundram et al 55 that nicely demonstrated the importance of FGF-2 and TGF-β for pericyte differentiation and the modulation of the blood-brain barrier integrity. Importantly, we found an overactivation of the TGF-β pathway in several different pulmonary vascular cells in remodeled PAH vessels, including in pulmonary pericytes.…”

Section: Ricard Et Al Pericytes In Pulmonary Arterial Hypertension 1593supporting

confidence: 93%

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

et al. 2014

View full text Add to dashboard Cite

P ulmonary arterial hypertension (PAH) is a rapidly progressive disease characterized by obstructive remodeling of distal pulmonary arteries (<500 μm), leading to a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. There is currently no cure for PAH, which has a very poor prognosis (mean survival of 2.8 years).1 It is well known that pulmonary arteries display complex structural and functional changes in PAH and that pulmonary endothelial cell (EC) dysfunction plays a crucial role in the disease progression. Despite an increased knowledge in the past years about PAH pathobiological cellular and molecular mechanisms, we still do not know what initiates this disease and its characteristic pulmonary vascular remodeling. Editorial see p 1545 Clinical Perspective on p 1597Pericytes are central regulators of vascular development, stabilization, maturation, and remodeling, modulating EC Background-Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. Methods and Results-In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Conclusions-To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. 10 In particular, pericytes that are found along arterioles and capillaries express different degrees...

show abstract

Section: Ricard Et Al Pericytes In Pulmonary Arterial Hypertension 1593supporting

confidence: 93%

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Our coculture model has been characterized on 0.4-μm-pore inserts; it exhibits features of the BBB such as low permeability to small, hydrophilic molecules, and the expression of continuous tight junctions and specific BBB transporters and receptors. 11 As with other in vitro BBB models, it combines ECs with the brain microvascular pericytes [20][21][22][23] known to be involved in BBB formation and maintenance in vivo. 24,25 Unfortunately, when this original model was transposed to 3-μm-pore inserts, the ECs crossed the porous membrane to form a second layer on the lower face.…”

Section: Discussionmentioning

confidence: 99%

Adapting coculture in vitro models of the blood–brain barrier for use in cancer research: maintaining an appropriate endothelial monolayer for the assessment of transendothelial migration

Vandenhaute¹,

Drolez²,

Sevin³

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Although brain metastases are the most common brain tumors in adults, there are few treatment options in this setting. To colonize the brain, circulating tumor cells must cross the blood-brain barrier (BBB), which is situated within specialized, restrictive microvascular endothelium. Understanding how cancer cells manage to transmigrate through the BBB might enable this process to be prevented. In vitro models are dedicated tools for characterizing the cellular and molecular mechanisms that underlie transendothelial migration process, as long as they accurately mimic the brain endothelium's in vivo characteristics. The objective of the present study was to adapt an existing in vitro model of the human BBB for use in studying cancer cell transmigration. The model is based on the coculture of endothelial cells (ECs, derived from cord blood hematopoietic stem cells) and brain pericytes. To allow the migration of cancer cells into the lower compartment, our model had to be transposed onto inserts with a larger pore size. However, we encountered a problem when culturing ECs on large (3-μm)-pore inserts: the cells crossed the membrane and formed a non-physiological second layer on the lower face of the insert. Using 3-μm-pore inserts (in a 12-well plate format), we report here on a method that enables the maintenance of a single monolayer of ECs on the insert's upper face only. Under these chosen conditions, the ECs exhibited typical BBB properties found in the original model (including restricted paracellular permeability and the expression of continuous tight junctions). This modified in vitro model of the human BBB enabled us to investigate the migratory potential of the MDA-MB-231 cell line (derived from highly metastatic human breast cancer cells). Last, the results obtained were compared with the rate of transmigration through endothelia with no BBB features.

show abstract

“…The regulation of BBB integrity by pericytes is of increasing interest due to the fact that these cells are in close proximity to brain endothelium and release a large number of endothelial permeability-regulating molecules. Pericytes are known to secrete elevated levels of permeability-inducing factors such as TNF-␣, IL-1␤, IL-6, metalloproteinases, and VEGF under different conditions (19)(20)(21)(22)24). These factors were elevated in JEV-infected animals and cultured glial cells (10,11,15,31,(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

“…Further evidence has demonstrated that the BBB is not intrinsic to the endothelial cells but is regulated by interactions with neighboring cells. Brain pericytes, the nearest neighbors of brain microvascular endothelial cells sharing a common basal membrane in cerebral capillaries, have a regulatory effect on BBB integrity (19)(20)(21). Virus-infected or stressed pericytes produced elevated levels of proinflammatory cytokines and compromised the integrity of the BBB in vitro (22)(23)(24).…”

mentioning

confidence: 99%

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

J Virol

View full text Add to dashboard Cite

h Though the compromised blood-brain barrier (BBB) is a pathological hallmark of Japanese encephalitis-associated neurological sequelae, the underlying mechanisms and the specific cell types involved are not understood. BBB characteristics are induced and maintained by cross talk between brain microvascular endothelial cells and neighboring elements of the neurovascular unit. In this study, we show a potential mechanism of disruption of endothelial barrier integrity during the course of Japanese encephalitis virus (JEV) infection through the activation of neighboring pericytes. We found that cultured brain pericytes were susceptible to JEV infection but were without signs of remarkable cytotoxicity. JEV-infected pericytes were found to release biologically active molecules which activated ubiquitin proteasome, degraded zonula occludens-1 (ZO-1), and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. Infection of pericytes with JEV was found to elicit elevated production of interleukin-6 (IL-6), which contributed to the aforementioned endothelial changes. We further demonstrated that ubiquitin-protein ligase E3 component n-recognin-1 (Ubr 1) was a key upstream regulator which caused proteasomal degradation of ZO-1 downstream of IL-6 signaling. During JEV central nervous system trafficking, endothelial cells rather than pericytes are directly exposed to cell-free viruses in the peripheral bloodstream. Therefore, the results of this study suggest that subsequent to primary infection of endothelial cells, JEV infection of pericytes might contribute to the initiation and/or augmentation of Japanese encephalitis-associated BBB breakdown in concerted action with other unidentified barrier disrupting factors.

show abstract

The impact of pericytes on the blood–brain barrier integrity depends critically on the pericyte differentiation stage

Cited by 108 publications

References 35 publications

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

Adapting coculture in vitro models of the blood–brain barrier for use in cancer research: maintaining an appropriate endothelial monolayer for the assessment of transendothelial migration

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Contact Info

Product

Resources

About