Notch Signaling in Vascular Endothelial and Mural Cell Communications

O’Hare, Michael; Arboleda‐Velásquez, Joseph F.

doi:10.1101/cshperspect.a041159

Cited by 6 publications

(2 citation statements)

References 128 publications

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“…The NOTCH3-JAG1 interaction is focused on in CADASIL research, because Jagged1 is expressed in both endothelial cells and VSMCs, and the co-expression of JAG1 and NOTCH3 was detected in adult humans [53]. Notch signaling in the crosstalk between VSMCs and endothelial cells is considered to play an important role in VSMC maturation [63]. Endothelial or VSMC-specific deletion in mice strongly suggests that NOTCH3-JAG1 interaction occurs between endothelial cells and VSMCs and also between neighboring VSMCs.…”

Section: Localization Of Notch Family Members and Their Ligands In Ve...mentioning

confidence: 99%

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease

Mizuta,

Nakao-Azuma,

Yoshida

et al. 2024

Biomolecules

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Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

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Section: Localization Of Notch Family Members and Their Ligands In Ve...mentioning

confidence: 99%

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease

Mizuta,

Nakao-Azuma,

Yoshida

et al. 2024

Biomolecules

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“…These data support the need for further investigation of mechanisms related to Notch especially in the early stages of disease progression. These studies could include Notch associated mechanisms related to sprouting and splitting angiogenesis induced by ischaemia in the micro-environment [52,53]. One study exemplifying possible approaches investigated the angiogenic factor canopy 2 in a mouse pressure overload model and reported that expression of the factor produced beneficial effects in the progression from hypertrophy to dilated failure [54].…”

Section: Notch Signalling Ischaemia and Microvascular Dysfunction In ...mentioning

confidence: 99%

A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies

Langa¹,

Shafaattalab

Goldspink³

et al. 2023

Phil. Trans. R. Soc. B

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In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding mutant proteins of the sarcomere. We recently reported an upregulation of elements in the Notch signalling cascade in cardiomyocytes derived from human inducible pluripotent stem cells expressing a TNNT2 variant encoding cardiac troponin T (cTnT-I79N +/− ), which induces hypertrophy, remodelling, abnormalities in excitation–contraction coupling and electrical instabilities (Shafaattalab S et al. 2021 Front . Cell Dev. Biol . 9 , 787581. ( doi:10.3389/fcell.2021.787581 )). Our search of the literature revealed the novelty of this finding and stimulated us to discuss potential connections between the Notch signalling pathway and familial cardiomyopathies. Our considerations focused on the potential role of these interactions in arrhythmias, microvascular ischaemia, and fibrosis. This finding underscored a need to consider the role of Notch signalling in familial cardiomyopathies which are trigged by sarcomere mutations engaging mechano-signalling pathways for which there is evidence of a role for Notch signalling with crosstalk with Hippo signalling. Our discussion included a role for both cardiac myocytes and non-cardiac myocytes in progression of HCM and DCM. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Blood vessel organoids generated by base editing and harboring single nucleotide variation in Notch3 effectively recapitulate CADASIL-related pathogenesis

Ahn,

An,

Yang

et al. 2024

Mol Neurobiol

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Human blood vessel organoids (hBVOs) offer a promising platform for investigating vascular diseases and identifying therapeutic targets. In this study, we focused on in vitro modeling and therapeutic target finding of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary stroke disorder caused by mutations in the NOTCH3 gene. Despite the identification of these mutations, the underlying pathological mechanism is elusive, and effective therapeutic approaches are lacking. CADASIL primarily affects the blood vessels in the brain, leading to ischemic strokes, migraines, and dementia. By employing CRISPR/Cas9 base-editing technology, we generated human induced pluripotent stem cells (hiPSCs) carrying Notch3 mutations. These mutant hiPSCs were differentiated into hBVOs. The NOTCH3 mutated hBVOs exhibited CADASIL-like pathology, characterized by a reduced vessel diameter and degeneration of mural cells. Furthermore, we observed an accumulation of Notch3 extracellular domain (Notch3ECD), increased apoptosis, and cytoskeletal alterations in the NOTCH3 mutant hBVOs. Notably, treatment with ROCK inhibitors partially restored the disconnection between endothelial cells and mural cells in the mutant hBVOs. These findings shed light on the pathogenesis of CADASIL and highlight the potential of hBVOs for studying and developing therapeutic interventions for this debilitating human vascular disorder.

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Notch Signaling in Vascular Endothelial and Mural Cell Communications

Cited by 6 publications

References 128 publications

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease

A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies

Blood vessel organoids generated by base editing and harboring single nucleotide variation in Notch3 effectively recapitulate CADASIL-related pathogenesis

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