Pericytes in Hereditary Hemorrhagic Telangiectasia

Galaris, Georgios; Thalgott, Jérémy H.; Lebrin, Franck

doi:10.1007/978-3-030-16908-4_10

Cited by 7 publications

(5 citation statements)

References 129 publications

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“…Pericytes promote vascular structural stability and protect the brain from blood-borne elements and bleeding phenomena [59]. Anomalies involving pericytes biology have been proven to play key roles in the etiopathogenesis of different genetic diseases characterized by psychiatric comorbidities, including the Hereditary Hemorrhagic Telangiectasia [65,66], a vascular dysplasia condition affecting one in 5000 people worldwide, and the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [67,68], the most commonly inherited small-vessel disease. Furthermore, pericytes paucity has been recently found associated with intraventricular hemorrhage of the germinal matrix (GH-IVH), both in premature humans and in a rabbit premature pup model [69].…”

Section: The Case Of Pericytesmentioning

confidence: 99%

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID‐19‐babies

et al. 2021

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Intragravidic and perinatal infections, acting through either direct viral effect or immune-mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up-to-date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID-19 longitudinal studies.

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Section: The Case Of Pericytesmentioning

confidence: 99%

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID‐19‐babies

et al. 2021

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“…However, under microfluidic flow, HHT-specific defective vascular organization was observed, accompanied by clear evidence of vascular leakage. Although haploinsufficiency is accepted as the primary mechanism underlying HHT1, it fails to account fully for the variability in clinical manifestations inter- and intra-families, nor does it explain the selective impact on specific vascular beds despite the ubiquitous presence of mutated genes across the vasculature [ 33 , 34 ]. There is reportedly a critical threshold of endoglin expression, below which ECs exhibit inadequate responses to environmental stimuli and become highly susceptible to HHT1 mutation.…”

Section: Discussionmentioning

confidence: 99%

Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT)

Koh,

Kang,

Mao

et al. 2024

Cell Biosci

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Background In vitro disease modeling enables translational research by providing insight into disease pathophysiology and molecular mechanisms, leading to the development of novel therapeutics. Nevertheless, in vitro systems have limitations for recapitulating the complexity of tissues, and a single model system is insufficient to gain a comprehensive understanding of a disease. Results Here we explored the potential of using several models in combination to provide mechanistic insight into hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder. Genome editing was performed to establish hPSCs (H9) with ENG haploinsufficiency and several in vitro models were used to recapitulate the functional aspects of the cells that constitute blood vessels. In a 2D culture system, endothelial cells showed early senescence, reduced viability, and heightened susceptibility to apoptotic insults, and smooth muscle cells (SMCs) exhibited similar behavior to their wild-type counterparts. Features of HHT were evident in 3D blood-vessel organoid systems, including thickening of capillary structures, decreased interaction between ECs and surrounding SMCs, and reduced cell viability. Features of ENG haploinsufficiency were observed in arterial and venous EC subtypes, with arterial ECs showing significant impairments. Molecular biological approaches confirmed the significant downregulation of Notch signaling in HHT-ECs. Conclusions Overall, we demonstrated refined research strategies to enhance our comprehension of HHT, providing valuable insights for pathogenic analysis and the exploration of innovative therapeutic interventions. Additionally, these results underscore the importance of employing diverse in vitro systems to assess multiple aspects of disease, which is challenging using a single in vitro system.

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“…HHT patients develop Arteriovenous Malformations (AVMs) that form when arterioles and veins connect directly without intervening blood capillaries. These vascular lesions can cause life-threatening complications such as hypoxemia, stroke, brain abscess, heart failure and fatal hemorrhage [1,2]. Many patients with HHT also suffer spontaneous, recurrent and severe nose and gastrointestinal bleeding, requiring regular iron and blood transfusions.…”

Section: Introductionmentioning

confidence: 99%

“…Many patients with HHT also suffer spontaneous, recurrent and severe nose and gastrointestinal bleeding, requiring regular iron and blood transfusions. The bleeding occurs because small AVMs (also called telangiectases) found in the skin, nasal septum, oral mucosa and in the gastrointestinal tract are particularly prone to hemorrhage [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…All gene mutations, whether deletion, insertion or missense mutations, as well as splice site changes, give rise to null alleles; the mutated genes are, thus, functionally inconsequential. Haploinsufficiency is therefore widely accepted as the underlying mechanism for HHT1, the remaining wild-type allele being unable to produce sufficient protein at the cell surface to sustain endothelial cell functions [1,2]. However, the haploinsufficiency model does not explain the high inter and intra familial variation in clinical manifestations, the age of onset of the disease and why only selected vascular beds are affected, as the mutated genes are present in vasculature throughout the body.…”

Section: Introductionmentioning

confidence: 99%

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Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1

Galaris

Montagne

Thalgott

et al. 2021

IJMS

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Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

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Pericytes in Hereditary Hemorrhagic Telangiectasia

Cited by 7 publications

References 129 publications

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID‐19‐babies

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID‐19‐babies

Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT)

Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1

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