KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses

Finetti, Federica; Schiavo, Irene; Ercoli, Jasmine; Zotta, Alessia; Boda, Enrica; Retta, Saverio Francesco; Trabalzini, Lorenza

doi:10.1016/j.cellsig.2020.109527

Cited by 17 publications

(12 citation statements)

References 51 publications

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“…Recent studies have shown that loss of CCM genes in neuroglia or stromal cells may contribute to CCM pathogenesis through non-cell-autonomous mechanisms (18,20,21). Although CCM is a disease that affects the neurovascular unit, there is a limited understanding of the crosstalk between the CCM endothelium and astrocytes, (20,22,23).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Lopez-Ramirez¹,

Lai²,

Soliman³

et al. 2021

Journal of Clinical Investigation

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by lossof-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1a in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1a target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

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Section: Introductionmentioning

confidence: 99%

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Lopez-Ramirez¹,

Lai²,

Soliman³

et al. 2021

Journal of Clinical Investigation

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“…In addition, Ccm3 loss in brain pericytes reduced their migration and association with endothelial cells [36] . Finally, very recently, Lopez-Ramirez et al [37] proposed an interesting model in which the crosstalk between astrocytes and endothelial cells drives vascular lesion formations. They showed that astrocytes are the major source of VEGF during CCM development.…”

Section: Non-autonomous Effects Of Ccm Gene Lossmentioning

confidence: 99%

“…The elevation of NO production by endothelium is due to endothelial nitric oxide increasing after the elevation of the transcription factors KLF2 and KLF4, previously implicated in the CCM pathogenesis. In addition, they showed that the inhibition of cyclooxygenase-2 (COX-2), a HIF-1α regulated gene, ameliorates the development of CCM lesions in animal models [37] . These data confirm that CCM3 deficient stromal cells In this context, we recently demonstrated that Krit1 deficient stromal cells are able to promote the activation of non-mutated endothelial cells by inducing their proliferation and migration [38] .…”

Section: Non-autonomous Effects Of Ccm Gene Lossmentioning

confidence: 99%

“…In addition CCM3 loss promotes increased VEGFR and epidermal growth factor receptor expression in both endothelial and non-endothelial cells [47] . In this scenario, VEGF and PGE2 appear as good candidates to promote the angiogenic switch of quiescent endothelial cells, and VEGF or PGE2 production or signaling cascade inhibition may represent good candidates for CCM therapy [37,38,48] .…”

Section: Promotion Of Angiogenesis After Ccm Gene Lossmentioning

confidence: 99%

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Non-autonomous effects of CCM genes loss

Finetti¹,

Trabalzini²

2021

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Cerebral cavernous malformation (CCM) is a rare disease of proven genetic origin characterized by vascular lesions affecting capillaries and small vessels of the central nervous system. CCM lesions occur in a range of different phenotypes, including wide differences in lesion number, size, and susceptibility to intracerebral hemorrhage. CCM lesion genesis requires loss of function of any of three genes, namely KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). These genes exert pleiotropic effects regulating multiple mechanisms involved in angiogenesis, cellular response, cell-cell and cell-matrix adhesion, cytoskeleton dynamics, and oxidative damage protection. Familial CCM is an autosomal-dominantly inherited disease in which the loss of any of the three CCM genes follows a two-hit mechanism. The heterozygous loss-of-function germline variants in one of the involved genes seems to be associated with a second postzygotic mutation, according to Knudson's two-hit model of tumor suppressor genes. This review is an overview of very recent literature on CCM onset and progression focused on the novel concept that the loss of a CCM gene in a single cell is sufficient to induce vascular lesions. Mutated cells undergo clonal expansion and become able to promote the recruitment of non-mutated cells and to induce their angiogenic switch through the increased production of angiogenic factors and downregulation of antiangiogenic factors. A deep understanding of this process and the knowledge of unbalanced secreted factors will be useful to design new pharmacological strategies for CCM patients.

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“…Recent studies have shown that loss of CCM genes in neuroglia or stromal cells may contribute to CCM pathogenesis through non-cell-autonomous mechanisms (16–18). Although CCM is a disease that affects the neurovascular unit, there is a limited understanding of the crosstalk between the CCM endothelium and astrocytes, (17, 19, 20).…”

Section: Introductionmentioning

confidence: 99%

Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

Ma¹,

Si²,

Hale³

et al. 2021

Preprint

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we report that proliferative astrocytes play a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilizes HIF-1α in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We show that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributes to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevents progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

show abstract

KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses

Cited by 17 publications

References 51 publications

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Non-autonomous effects of CCM genes loss

Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

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