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mTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis.
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- Additional Information
- Source:
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
- Publication Information:
Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.
- Subject Terms:
- Abstract:
Background: Cerebral vascular malformations (CCMs) are primarily found within the 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 formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are 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 events in the subclass of brain ECs/EPCs for CCM lesion initiation and progression are unclear.
Methods: Brain EC-specific CCM3-deficient ( Pdcd10 BECKO ) mice were generated by crossing Pdcd10 fl/fl mice with Mfsd2a -CreER T2 mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10× genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches.
Results: Single-cell RNA-sequencing analyses from P10 Pdcd1 0 BECKO mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier-associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6 Pdcd1 0 BECKO brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the Pdcd10 BECKO model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in Pdcd10 BECKO mice. Mechanistic studies suggested that Cav1/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins.
Conclusions: CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss-induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis.
Competing Interests: None.
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- Grant Information:
R01 EY033333 United States EY NEI NIH HHS; R01 HL157019 United States HL NHLBI NIH HHS; R50 CA265359 United States CA NCI NIH HHS
- Contributed Indexing:
Keywords: TOR serine-threonine kinases; blood–brain barrier; caveolae; endocytosis; hemangioma, cavernous, central nervous system; mechanistic target of rapamycin complex 1; single-cell gene expression analysis
- Accession Number:
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
0 (PDCD10 protein, mouse)
0 (Apoptosis Regulatory Proteins)
0 (Membrane Proteins)
- Publication Date:
Date Created: 20240703 Date Completed: 20240801 Latest Revision: 20240804
- Publication Date:
20240804
- Accession Number:
PMC11293987
- Accession Number:
10.1161/CIRCRESAHA.123.324015
- Accession Number:
38957991
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