CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype

Vannier, Daphné; Shapeti, Apeksha; Chuffart, Florent; Planus, Emmanuelle; Manet, Sandra; Rivier, Paul; Destaing, Olivier; Albigès-Rizo, Corinne; Oosterwyck, Hans Van; Faurobert, Eva

doi:10.1007/s10456-021-09809-2

Cited by 14 publications

(24 citation statements)

References 78 publications

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“…1 b) were both upregulated. These findings were also confirmed by transcriptomic data from siCCM2 -treated HUVECs 35 . Interestingly, another common finding in all three CCM models was the simultaneous upregulation of genes encoding RA degrading enzymes Cyp26A or Cyp26B (Fig.…”

Section: Resultssupporting

confidence: 67%

“…Based on the differentially expressed genes in mice, we data mined the published CCM2-knock-out zebrafish dataset, which was based on whole heart tissue 34 . The same was done for siCCM2 -treated HUVECs, for which transcriptomic data had recently been published 35 . Fold changes of genes of interest were visualized by grouped sizes of circles and plotted on a chart in an alphabetical order.…”

Section: Methodsmentioning

confidence: 99%

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Impaired retinoic acid signaling in cerebral cavernous malformations

Grdseloff

Boulday

Rödel

et al. 2023

Sci Rep

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The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes.

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Section: Resultssupporting

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Impaired retinoic acid signaling in cerebral cavernous malformations

Grdseloff

Boulday

Rödel

et al. 2023

Sci Rep

Self Cite

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“…CCM3 mutations tend to appear earlier with a more severe pathobiology [ 254 ]. Interestingly, CCM mutations result in RhoA and RhoA kinase (ROCK) activation which impairs EC barrier function and promotes a senescence-associated secretory phenotype; statins and drugs that inhibit ROCK can reduce CCM lesions in mice [ 255 , 256 ]. Many CCM lesions present as hyperpermeable tangles of vessels that resemble transformed ECs in vascular-derived malignancies such as hemangiosarcoma.…”

Section: Angiogenesis and Anti-angiogenesis In Diseasesmentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

118

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In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

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“…Vannier et al reported the loss of CCM1 and CCM2 in endothelial cells (HUVECs) triggers them to transition to a senescence-associated secretory phenotype via activation of Rho-associated coiled-coil containing protein kinase 2 (ROCK2). The authors had also proposed that the SASP changes the tissue microenvironment by increasing extracellular matrix degradation (Vannier et al, 2021). Kiss and colleagues identified senescent cerebromicrovascular endothelial cells in the aged mouse brain using complex analyses of single-cell RNA sequencing data (Kiss et al, 2020).…”

Section: Endothelial Senescence In Diabetes and Metabolic Diseasesmentioning

confidence: 99%

Cerebral Microvascular Senescence and Inflammation in Diabetes

2022

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Stress-induced premature senescence can contribute to the accelerated metabolic aging process in diabetes. Progressive accumulation of senescent cells in the brain, especially those displaying the harmful inflammatory senescence-associated secretory phenotype (SASP), may lead to cognitive impairment linked with metabolic disturbances. In this context, the senescence within the neurovascular unit (NVU) should be studied as much as in the neurons as emerging evidence shows that neurogliovascular communication is critical for brain health. It is also known that cerebrovascular dysfunction and decreased cerebral blood flow (CBF) precede the occurrence of neuronal pathologies and overt cognitive impairment. Various studies have shown that endothelial cells, the major component of the NVU, acquire a senescent phenotype via various molecular mediators and pathways upon exposure to high glucose and other conditions mimicking metabolic disturbances. In addition, senescence in the other cells that are part of the NVU, like pericytes and vascular smooth cells, was also triggered upon exposure to diabetic conditions. The senescence within the NVU may compromise functional and trophic coupling among glial, vascular, and neuronal cells and the resulting SASP may contribute to the chronic neurovascular inflammation observed in Alzheimer’s Disease and Related Dementias (ADRD). The link between diabetes-mediated cerebral microvascular dysfunction, NVU senescence, inflammation, and cognitive impairment must be widely studied to design therapeutic strategies.

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CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype

Cited by 14 publications

References 78 publications

Impaired retinoic acid signaling in cerebral cavernous malformations

Impaired retinoic acid signaling in cerebral cavernous malformations

Pathological angiogenesis: mechanisms and therapeutic strategies

Cerebral Microvascular Senescence and Inflammation in Diabetes

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