A single nuclear transcriptomic characterization of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252921 | GEO | 2024/01/20
REPOSITORIES: GEO
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Project description:The receptor tyrosine kinase Mer (gene name Mertk) acts in vascular endothelial cells (ECs) to tighten the blood-brain barrier (BBB) subsequent to viral infection. Correspondingly, we found that Mer regulates the expression and activity of a large cohort of cytoskeletal and BBB proteins, together with endothelial nitric oxide synthase, in brain ECs. We further found that Mer controls the expression of multiple angiogenic genes, and that EC-specific Mertk gene inactivation results in perturbed vascular sprouting and a compromised BBB after induced photothrombotic stroke. Unexpectedly, stroke lesions in the brain were also markedly reduced in the absence of EC Mer, which was linked to reduced plasma expression of fibrinogen, prothrombin, and other effectors of blood coagulation. Together, these results demonstrate that Mer is a central regulator of angiogenesis, BBB integrity, and blood coagulation in the mature vasculature. They may also account for disease severity following infection with the coronavirus SARS-CoV-2.
2023-02-23 | MSV000091355 | MassIVE
Project description:With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed – the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions. Furthermore, an overrepresentation of Alzheimer’s disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study revealed novel vascular ageing-associations of AD in the brain capillary endothelium, and provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.
2020-03-30 | GSE147693 | GEO
Project description:The receptor tyrosine kinase Mer (gene name Mertk) acts in vascular endothelial cells (ECs) to tighten the blood-brain barrier (BBB) subsequent to viral infection. Correspondingly, we found that Mer regulates the expression and activity of a large cohort of cytoskeletal and BBB proteins, together with endothelial nitric oxide synthase, in brain ECs. We further found that Mer controls the expression of multiple angiogenic genes, and that EC-specific Mertk gene inactivation results in perturbed vascular sprouting and a compromised BBB after induced photothrombotic stroke. Unexpectedly, stroke lesions in the brain were also markedly reduced in the absence of EC Mer, which was linked to reduced plasma expression of fibrinogen, prothrombin, and other effectors of blood coagulation. Together, these results demonstrate that Mer is a central regulator of angiogenesis, BBB integrity, and blood coagulation in the mature vasculature. They may also account for disease severity following infection with the coronavirus SARS-CoV-2.
2023-08-24 | GSE225474 | GEO
Project description:Cerebral vascular malformations (CCM) are primarily found within brain, where they result in increased risk for stroke, seizures and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier (BBB) formed by the brain neurovascular unit, and recent studies suggest that loss of CCM genes causes disruptions of BBB integrity as the inciting event for the development of CCM. CCM lesion is proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling in the subclass of brain EC/EPC for the CCM lesion initiation and progression are unclear. Here we employed single-cell RNA-sequencing (scRNA-seq) analyses in early stages of the brain EC-specific Ccm3 deletion (Pdcd10BECKO) microvessels and identified a unique EPC cluster with high stem cell markers but low BBB-associated genes. mTORC1, but not mTORC2, is activated in mouse and human CCM lesions and EPCs. Mechanistic studies suggest that CCM3 suppresses Cav1/caveolae-mediated cellular trafficking and complex formation of the mTORC1 signaling proteins. Genetic deficiency of Raptor (mTORC1), but not of Rictor (mTORC2), prevents CCM lesion formation in the Pdcd10BECKO model. Importantly, mTORC1 pharmacological inhibitor Rapamycin ameliorate the CCM pathogenesis in the Pdcd10BECKO mice, by suppressing lesion-forming EPC expansion while enhancing BBB maturation. Our data suggest that CCM3 is critical for maintaining BBB integrity, and CCM3 loss-induced mTORC1 signaling in brain EPCs initiate the CCM pathogenesis.
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Project description:The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.
2021-09-01 | GSE179372 | GEO
Project description:Pericytes (PCs) are microvascular mural cells which constituent the embryonic blood brain barrier (BBB) along with endothelial cells (ECs). During brain development, germinal matrix (GM) - a highly vascularized region rich in neuronal-glial precursors, is selectively vulnerable to hemorrhage in premature infants. The transforming growth factor β (TGFβ) pathway plays a crucial role in barrier development by regulating cellular cross talk between PCs and ECs. Indeed, murine embryos lacking TGFβ receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) and culminate in perinatal lethality. Mutant GM vessels display reduced PC and collagen coverage, abnormal vessel dilation and EC hyperproliferation. However, the mechanistic link between PC-specific deletion of ALK5 and aberrant EC behavior remains elusive. Herein, using bulk RNA sequencing from human brain PCs lacking ALK5 (siALK5) as well as murine vascular cells [PCs and ECs] isolated from embryonic brain at embryonic days E11.5 and E13.5 we establish that angiopoietin 2 (ANGPT2), a secreted angiogenic growth factor, is robustly repressed by the TGFβ pathway in PCs. Conversely, mutants lacking PC-ALK5 secrete higher levels of ANGPT2 resulting in overactivation of tyrosine protein kinase receptor (TIE2) and culminating in EC hyperproliferation, vessel dilation, BBB breakdown and GMH. PC-specific Angpt2 deletion or pharmacological inhibition in mutants improves GM vessel morphology, reduces EC proliferation and attenuates GMH pathogenesis. Taken together, we demonstrate that loss of TGFβ-mediated ANGPT2 repression in PCs is detrimental for BBB integrity and identify ANGPT2 as an important pathological target for GMH-IVH.
2024-06-30 | GSE269066 | GEO
Project description:Pericytes (PCs) are microvascular mural cells which constituent the embryonic blood brain barrier (BBB) along with endothelial cells (ECs). During brain development, germinal matrix (GM) - a highly vascularized region rich in neuronal-glial precursors, is selectively vulnerable to hemorrhage in premature infants. The transforming growth factor β (TGFβ) pathway plays a crucial role in barrier development by regulating cellular cross talk between PCs and ECs. Indeed, murine embryos lacking TGFβ receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) and culminate in perinatal lethality. Mutant GM vessels display reduced PC and collagen coverage, abnormal vessel dilation and EC hyperproliferation. However, the mechanistic link between PC-specific deletion of ALK5 and aberrant EC behavior remains elusive. Herein, using bulk RNA sequencing from human brain PCs lacking ALK5 (siALK5) as well as murine vascular cells [PCs and ECs] isolated from embryonic brain at embryonic days E11.5 and E13.5 we establish that angiopoietin 2 (ANGPT2), a secreted angiogenic growth factor, is robustly repressed by the TGFβ pathway in PCs. Conversely, mutants lacking PC-ALK5 secrete higher levels of ANGPT2 resulting in overactivation of tyrosine protein kinase receptor (TIE2) and culminating in EC hyperproliferation, vessel dilation, BBB breakdown and GMH. PC-specific Angpt2 deletion or pharmacological inhibition in mutants improves GM vessel morphology, reduces EC proliferation and attenuates GMH pathogenesis. Taken together, we demonstrate that loss of TGFβ-mediated ANGPT2 repression in PCs is detrimental for BBB integrity and identify ANGPT2 as an important pathological target for GMH-IVH.
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2022-08-31 | GSE207106 | GEO