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An organ-specific angiogenic control mechanism for endothelial tailoring

ABSTRACT: Each organ of the human body requires locally-adapted blood vessels. The gain of such organotypic vessel specializations is often deemed molecularly unrelated to the process of organ vascularization. Opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis, that operates under the control of Wnt7a/b ligands, well-known blood-brain barrier maturation signals. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25 in brain endothelial cells. This hitherto poorly characterized GPI-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane lining the brain surface, which distinctive molecular composition is controlled by embryonic pial fibroblasts. Mechanistically, Mmp25 confers brain invasive competence by cleaving the pial basement membrane-enriched Col4a5/6 within a short non-collagenous region of the central helical part of the heterotrimer. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in properly patterned, yet blood-brain barrier-defective cerebrovasculatures. This work reveals an organ-specific angiogenesis mechanism, sheds light on tip cell mechanistic angiodiversity, and thereby illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.

ORGANISM(S): Danio rerio

PROVIDER: GSE233662 | GEO | 2024/02/08

REPOSITORIES: GEO

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An organ-specific angiogenic control mechanism for endothelial tailoring.

Project description:Each organ of the human body requires locally-adapted blood vessels1–3. The gain of such organotypic vessel specializations is often deemed molecularly unrelated to the process of organ vascularization. Opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis that operates under the control of Wnt7a/b ligands, well-known blood-brain barrier maturation signals4–6. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25 in brain endothelial cells. This hitherto poorly characterized GPI-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane which lines the brain surface, and whose distinctive molecular composition is controlled by embryonic pial fibroblasts. Mechanistically, Mmp25 confers brain invasive competence by cleaving the pial basement membrane-enriched Col4a5/6 within a short non-collagenous region of the central helical part of the heterotrimer. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in a properly patterned, yet blood-brain barrier-defective cerebrovasculature. This work reveals an organ-specific angiogenesis mechanism, sheds light on tip cell mechanistic angiodiversity, and thereby illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.

2024-02-08 | PXD042613 | Pride

An integrated approach to profile lung tumor endothelial cell heterogeneity across species and models and to identify angiogenic candidates

Project description:Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse) and models (in vivo/vitro) remains poorly inventoried at the single-cell-level. We single-cell RNA-sequenced 56,771 ECs from human/mouse (peri)-tumoral lung and cultured human lung TECs, detected 17 known and discovered 16 novel phenotypes, including TECs presumably regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a novel basement-membrane remodeling breach phenotype. Tip-TEC signatures correlated with patient-survival, and tip/breach TECs were most sensitive to VEGF-blockade. By similarity analysis, only tip-TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-seq data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen-modification as angiogenic candidate pathway.

2019-12-30 | E-MTAB-6308 | biostudies-arrayexpress

An integrated approach to profile lung tumor endothelial cell heterogeneity across species and models and to identify angiogenic candidates

2020-05-20 | E-MTAB-7458 | biostudies-arrayexpress

An integrated approach to profile lung tumor endothelial cell heterogeneity across species and models and to identify angiogenic candidates

2020-03-07 | E-MTAB-8031 | biostudies-arrayexpress

Mesenchymal proteases and tissue fluidity remodel the extracellular matrix during airway epithelial branching in the embryonic avian lung

Project description:Reciprocal signaling between an epithelium and its surrounding mesenchyme is common during morphogenesis. These epithelial-mesenchymal interactions are particularly evident in tissues that undergo branching morphogenesis, such as the airway epithelium of the lung. Here, we found that reciprocal interactions between the epithelium and mesenchyme drive remodeling of the extracellular matrix (ECM) during morphogenesis of the embryonic chicken lung. RNA-Seq analysis revealed changes in the expression of genes associated with integrin signaling and ECM remodeling. Consistently, we found that prior to branching, the basement membrane is a spatially uniform sheath that wraps the airway epithelium. After branch initiation, however, the basement membrane is significantly depleted from the tip of extending branches. Culturing embryonic lung explants revealed that this basement membrane thinning is mediated by matrix metalloproteinase-2 (MMP2), which is expressed in the mesenchyme. Inhibiting MMP activity suppresses branch extension but has no effect on branch initiation. As branches extend, we found that tenascin-C (TNC) accumulates in the mesenchyme several cell diameters away from the branch tip. Despite its pattern of accumulation, this mesenchymal ECM protein is expressed exclusively by airway epithelial cells, which activate focal adhesion kinase (FAK) to induce TNC expression. We found that branch extension coincides with the deformation of adjacent mesenchymal cells into elongated geometries, which correlates with an increase in the fluidity of the mesenchyme at branch tips. This local increase in mesenchymal movement transports TNC from the epithelial surface into the mesenchyme. These data reveal novel epithelial-mesenchymal interactions that direct ECM remodeling during airway branching morphogenesis.

2019-08-12 | GSE132478 | GEO

Organotypic Human Epithelial Neoplasia

Project description:Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within an entirely human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane (BM). These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through the BM, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression. Organotypic human cervical epithium expressing LacZ, cdk4 and Ras, or cdk and Ras with U0126 mediated MEK inhibition were harvested for RNA extraction and hybridization on Affymetrix microarrays. There are 2 biologic replicates for each group.

2010-09-15 | E-GEOD-22382 | biostudies-arrayexpress

Organotpyic Human Epithelial Neoplasia

Project description:Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within an entirely human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane (BM). These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through the BM, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression. Organotypic human epidermal epithium expressing LacZ, cdk4 and Hras, or cdk and Ras with U0126 mediated MEK inhibition were harvested for RNA extraction and hybridization on Affymetrix microarrays. There are 8 biologic replicates for the LacZ, and cdk4 Ras groups, and 2 biologic replicates for the U0126 treated samples.

2010-10-15 | E-GEOD-22573 | biostudies-arrayexpress

miR-221 is required for endothelial tip cell behaviors during vascular development

Project description:Through deep sequencing and functional screening in zebrafish, we find that miR-221 is essential for angiogenesis. miR-221 knockdown phenocopied defects associated with loss of the tip cell-expressed Flt4 receptor. Furthermore, miR-221 was required for tip cell proliferation and migration, as well as tip cell potential in mosaic blood vessels. miR-221 knockdown also prevented “hyper-angiogenesis” defects associated with Notch deficiency and miR-221 expression was inhibited by Notch signaling. Finally, miR-221 promoted tip cell behavior through repression of two targets: cyclin-dependent kinase inhibitor 1b (cdkn1b) and phosphoinositide-3-kinase regulatory subunit 1 (pik3r1). These results identify miR-221 as an important regulatory node through which tip cell migration and proliferation are controlled during angiogenesis.

2012-02-28 | GSE35078 | GEO

Proteomic analysis of primary human microvascular endothelial cells (HMVECs) stimulated for 24â€‰h with either 50 ï�g/mL recombinant Fibrillin-1 C-terminal fragment or 25â€‰ng/ml VEGF-A compared to unstimulated cells.

Project description:Mutations in the fibrillin-1 gene result in cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here we show that a fibrillin-1 mutation also alters the neovessel formation. In the mouse retina vascularization model, fibrillin-1 is detected at the basement membrane underlying the angiogenic front and around arterioles. In Fbn1C1041G/+ mice, a model of Marfan disease, the microvasculature is altered at these sites. At the front, endothelial tip-cell sprouting and branching are decreased, and we show that mutant fibrillin-1 delays angiogenesis by affecting Notch signalling. Supplying the growing vasculature of Fbn1C1041G/+ mice with a C-terminal fragment of fibrillin-1 corrects all defects. In vitro, the C-terminal fragment of fibrillin-1 also displays pro-angiogenic activities on microvascular endothelial cell. Our data establish that fibrillin-1 performs essential functions in microvessel formation and integrity and that mutant fibrillin-1-induced defects can be rescued pharmacologically.

2023-05-31 | PXD029834 | Pride

miR-221 is required for endothelial tip cell behaviors during vascular development

2012-02-28 | E-GEOD-35078 | biostudies-arrayexpress

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