Foxc1 is required by pericytes during fetal brain angiogenesis.
Ontology highlight
ABSTRACT:
SUBMITTER: Siegenthaler JA
PROVIDER: S-EPMC3711032 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte-endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease.
| S-EPMC3241506 | biostudies-literature
Project description:Vascular physiology relies on the concerted dynamics of several cell types, including pericytes, endothelial, and vascular smooth muscle cells. The interactions between such cell types are inherently dynamic and are not easily described with static, fixed, experimental approaches. Pericytes are mural cells that support vascular development, remodeling, and homeostasis, and are involved in a number of pathological situations including cancer. The dynamic interplay between pericytes and endothelial cells is at the basis of vascular physiology and few experimental tools exist to properly describe and study it. Here we employ a previously developed ex vivo murine aortic explant to study the formation of new blood capillary-like structures close to physiological situation. We develop several mouse models to culture, identify, characterize, and follow simultaneously single endothelial cells and pericytes during angiogenesis. We employ microscopy and image analysis to dissect the interactions between cell types and the process of cellular recruitment on the newly forming vessel. We find that pericytes are recruited on the developing sprout by proliferation, migrate independently from endothelial cells, and can proliferate on the growing capillary. Our results help elucidating several relevant mechanisms of interactions between endothelial cells and pericytes.
| S-EPMC6770602 | biostudies-literature
Project description:For human brain pericytes, we used fetal cells passage 3 (ScienCell, San Diego, CA, USA ) seeded Pericyte medium (ScienCell, San Diego, CA, USA) at density 8-15000
cells/cm2 tissue culture plastic culture dishes coated with Attachment Factor for 30 min (Cell Systems, Kirkland, WA, USA). Further info in "Proteomic and metabolomic characterization of human neurovascular unit cells in response to methamphetamine" Herland et al Adv Biosystems 2020
2020-07-23 | MSV000085818 | GNPS
Project description:BackgroundThe complex endocrine and exocrine functionality of the human pancreas depends on an efficient fluid transport through the blood and the lymphatic vascular systems. The lymphatic vasculature has key roles in the physiology of the pancreas and in regulating the immune response, both important for developing successful transplantation and cell-replacement therapies to treat diabetes. However, little is known about how the lymphatic and blood systems develop in humans. Here, we investigated the establishment of these two vascular systems in human pancreas organogenesis in order to understand neovascularization in the context of emerging regenerative therapies.MethodsWe examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry.ResultsAs early as W9, the peri-pancreatic mesenchyme was populated by CD31-expressing blood vessels as well as LYVE1- and PDPN-expressing lymphatic vessels. The appearance of smooth muscle cell-coated blood vessels in the intra-pancreatic mesenchyme occurred only several weeks later and from W14.5 onwards the islets of Langerhans also became heavily irrigated by blood vessels. In contrast to blood vessels, LYVE1- and PDPN-expressing lymphatic vessels were restricted to the peri-pancreatic mesenchyme until later in development (W14.5-W17), and some of these invading lymphatic vessels contained smooth muscle cells at W17. Interestingly, between W11-W22, most large caliber lymphatic vessels were lined with a characteristic, discontinuous, collagen type IV-rich basement membrane. Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.ConclusionOur data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards. Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.
| S-EPMC4362646 | biostudies-literature
Project description:For human brain pericytes, we used fetal cells passage 3 (ScienCell, San Diego, CA, USA ) seeded Pericyte medium (ScienCell, San Diego, CA, USA) at density 8-15000
cells/cm2 tissue culture plastic culture dishes coated with Attachment Factor for 30 min (Cell Systems, Kirkland, WA, USA). Methamphetamine (Sigma-Aldrich, St Louis, MO, USA) was prepared at a stock concentration of 10mM in distilled water. Methamphetamine dilutions 50 micromolar were made in Endo and Neuro/Astro/Peri media respectively and applied to the cells for 26 hrs. Further info in "Proteomic and metabolomic characterization of human neurovascular unit cells in response to methamphetamine" Herland et al Adv Biosystems 2020
2020-07-23 | MSV000085820 | GNPS
Project description:Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor ? (PDGFR?), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFR? nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFR?(+) pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFR?(+) VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFR? in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFR? monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFR?(+) VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFR?. Taken together, these data indicate that PDGFR?(+) pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.
| S-EPMC3695363 | biostudies-literature
Project description:Pericytes/vascular smooth muscle cells (VSMCs), regulated by platelet-derived growth factor receptor β (PDGFRβ) signaling, play important roles in endothelial survival and vascular stability. Here we report that treatment with imatinib, an inhibitor of PDGFRβ, led to significant tumor growth impairment associated with increased apoptosis in human lymphoma xenografts including Farage, Karpas422 and OCI-Ly7 in SCID mice. Confocal analysis of the tumor tissue showed decreased microvessel density, decreased vascular flow, and increased vascular leak in the imatinib-treated cohorts. Imatinib targeted tumor-associated PDGFRβ+ pericytes in vivo by inducing apoptosis and disruption of the PDGFRβ+ perivascular network, and PDGFRβ+ VSMC in vitro by inhibition of proliferation. FACS analysis of mononuclear cell suspension of tumor tissues revealed decreased mature pericytes and endothelial cells, as well as their progenitors with imatinib treatment. Compared to imatinib, treatment with anti-PDGFRβ monoclonal antibody partially inhibited the growth of Farage lymphomas. Lastly, microarray analysis of differentially expressed genes in PDGFRβ+ VSMC following imatinib treatment showed significant down-regulation of genes implicated in proliferation, survival and angiogenesis, including those within PI3K/AKT and MAPK/ERK1/2 pathways downstream of PDGFRβ signaling. Taken together, targeting PDGFRβ+ pericytes in lymphoma presents a novel and complementary target to endothelial cells for efficacious antiangiogenic therapy. PDGFRb+ murine vascular smooth muscle cells (VSMCs) were treated in 10 uM imatinib for 24 or 48 hours. Gene expression changes in response to imatinib treatment were examined using NimbleGen MM8_60mer gene expression microarrays by comparing expression patterns at 24- and 48-hours treatment to the baseline level (0 hours).
2013-04-22 | E-GEOD-30752 | biostudies-arrayexpress
Project description:Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.
| S-EPMC3056408 | biostudies-literature
Project description:Crosstalk mechanisms between pericytes, endothelial cells, and astrocytes preserve integrity and function of the blood-brain-barrier (BBB) under physiological conditions. Long intercellular channels allowing the transfer of small molecules and organelles between distant cells called tunneling nanotubes (TNT) represent a potential substrate for energy and matter exchanges between the tripartite cellular compartments of the BBB. However, the role of TNT across BBB cells under physiological conditions and in the course of BBB dysfunction is unknown. In this work, we analyzed the TNT's role in the functional dialog between human brain endothelial cells, and brain pericytes co-cultured with human astrocytes under normal conditions or after exposure to ischemia/reperfusion, a condition in which BBB breakdown occurs, and pericytes participate in the BBB repair. Using live time-lapse fluorescence microscopy and laser-scanning confocal microscopy, we found that astrocytes form long TNT with pericytes and endothelial cells and receive functional mitochondria from both cell types through this mechanism. The mitochondrial transfer also occurred in multicellular assembloids of human BBB that reproduce the three-dimensional architecture of the BBB. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and astrocytes exposed to oxygen-glucose deprivation were rescued from apoptosis by healthy pericytes through TNT-mediated transfer of functional mitochondria, an effect that was virtually abolished in the presence of TNT-destroying drugs. The results establish a functional role of TNT in the crosstalk between BBB cells and demonstrate that TNT-mediated mitochondrial transfer from pericytes rescues astrocytes from ischemia/reperfusion-induced apoptosis. Our data confirm that the pericytes might play a pivotal role in preserving the structural and functional integrity of BBB under physiological conditions and participate in BBB repair in brain diseases.
| S-EPMC9256725 | biostudies-literature
Project description:Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of proinflammatory and proangiogenic cues is only partially understood. Using an experimental model, permitting exposure of developing blood vessel sprouts to multiple combinations of diverse biochemical stimuli and juxtacrine cell interactions, we present evidence that a proinflammatory cytokine, tumor necrosis factor (TNF), can have both proangiogenic and antiangiogenic effects, depending on the dose and the presence of pericytes. In particular, we find that pericytes can rescue and enhance angiogenesis in the presence of otherwise-inhibitory high TNF doses. This sharp switch from proangiogenic to antiangiogenic effect of TNF observed with an escalating dose of this cytokine, as well as the effect of pericytes, are explained by a mathematical model trained on the biochemical data. Furthermore, this model was predictive of the effects of diverse combinations of proinflammatory and antiinflammatory cues, and variable pericyte coverage. The mechanism supports the effect of TNF and pericytes as modulating signaling networks impinging on Notch signaling and specification of the Tip and Stalk phenotypes. This integrative analysis elucidates the plasticity of the angiogenic morphogenesis in the presence of diverse and potentially conflicting cues, with immediate implications for many physiological and pathological settings.
| S-EPMC6876202 | biostudies-literature