Hepatic manifestations of hereditary haemorrhagic telangiectasia DOI Open Access
Claire Kelly, Elisabetta Buscarini, Guido Manfredi

et al.

Liver International, Journal Year: 2024, Volume and Issue: 44(9), P. 2220 - 2234

Published: June 7, 2024

Abstract Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance pro‐ and anti‐angiogenic products the transforming growth factor β/bone morphogenetic protein signalling pathway which contributes to vascular remodelling maintenance. Hepatic malformations are common although less frequently symptomatic, but may result in high‐output cardiac failure, portal hypertension biliary ischaemia. Whilst understanding cell pathways that hallmark hereditary have been clarified, there remain challenges therapy for these patients. Only patients with symptomatic hepatic require treatment, most (63%) responding first‐line medical therapy. For non‐responders, bevacizumab effective reducing output those heart failure secondary as well other manifestations disease. Although liver transplantation only curative option, optimal timing critical. Novel anti‐angiogenetic drugs target aberrant being explored.

Language: Английский

The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy DOI Open Access
Nicolas Ricard, Sabine Bailly, Christophe Guignabert

et al.

Nature Reviews Cardiology, Journal Year: 2021, Volume and Issue: 18(8), P. 565 - 580

Published: Feb. 24, 2021

Language: Английский

Citations

170
Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances DOI Creative Commons
Tala Al Tabosh, Mohammad Al Tarrass,

Laura Tourvieilhe

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(4)

Published: Feb. 14, 2024

Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease characterized by small arteriovenous malformations (AVMs) mucocutaneous areas (telangiectases) and larger visceral AVMs the lungs, liver, brain. HHT caused loss-of-function mutations BMP9-10/ENG/ALK1/SMAD4 signaling pathway. Review presents up-to-date insights on this mutated pathway its crosstalk proangiogenic pathways, particular VEGF pathway, that has allowed repurposing of new drugs for treatment. However, despite substantial benefits these treatments terms alleviating symptom severity, not-so-uncommon bleeding still currently lacks any FDA- or European Medicines Agency-approved (EMA-approved) therapies.

Language: Английский

Citations

20
Future treatments for hereditary hemorrhagic telangiectasia DOI Creative Commons
F. Robert, Agnès Desroches‐Castan, Sabine Bailly

et al.

Orphanet Journal of Rare Diseases, Journal Year: 2020, Volume and Issue: 15(1)

Published: Jan. 7, 2020

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000-8000 individuals worldwide. This rare disease characterized by various defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) several organs. About 90% of the cases are associated with heterozygous mutations ACVRL1 or ENG genes, that respectively encode bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) co-receptor named endoglin. Less frequent found remaining 10% patients affect gene SMAD4 which part transcriptional complex directly activated this pathway. Presently, therapeutic treatments for HHT intended to reduce symptoms disease. However, recent progress has been made using drugs target VEGF (vascular endothelial growth factor) angiogenic pathway use bevacizumab (anti-VEGF antibody). Furthermore, exciting high-throughput screenings preclinical studies have identified new molecular targets related signaling pathways affected These include FKBP12, PI3-kinase angiopoietin-2. review aims at reporting these developments should soon allow better care patients.

Language: Английский

Citations

107
Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia DOI Open Access
Hyojin Park, Jessica Furtado, Mathilde Poulet

et al.

Circulation, Journal Year: 2021, Volume and Issue: 144(10), P. 805 - 822

Published: June 29, 2021

Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations the

Language: Английский

Citations

88
Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment DOI Open Access
Katharina Schimmel, Md Khadem Ali, Serena Y. Tan

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 9037 - 9037

Published: Aug. 21, 2021

Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between artery and vein (bypassing the capillaries). These high flow lesions can vary in size location. Therapeutic approaches limited, AVMs cause significant morbidity mortality. Here, we describe our current understanding of pathogenesis arteriovenous based on preclinical clinical findings. We discuss past accomplishments challenges field identify research gaps that need to be filled for successful development therapeutic strategies future.

Language: Английский

Citations

63
Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression DOI Creative Commons
Kie Kyon Huang,

Haoran Ma,

Roxanne Hui Heng Chong

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2019 - 2037.e8

Published: Oct. 26, 2023

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased cancer (GC) risk. Analyzing 1,256 samples (1,152 IMs) across 692 subjects from prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell spatial profiles highlight changes tissue ecology lineage heterogeneity, an stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, microbial communities normally healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only predicting IMs likely transform GC. By highlighting strategies for accurately identifying patients at high GC risk role dysbiosis progression, our results raise opportunities precision prevention interception.

Language: Английский

Citations

40
Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations inSMAD4 DOI
Evon M. DeBose-Scarlett, Andrew K. Ressler, Cassi Friday

et al.

Journal of Medical Genetics, Journal Year: 2025, Volume and Issue: unknown, P. jmg - 110569

Published: Feb. 12, 2025

Background Hereditary haemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations. It caused by loss-of-function mutations in one three genes, ENG , ACVRL1 or SMAD4 . We recently showed that HHT-associated malformations from liver, lung, brain and skin develop via a two-hit genetic mechanism resulting biallelic either Second-hit somatic have not been reported Here, we investigate large, aggressively growing craniofacial arteriovenous malformation (AVM) individual with juvenile polyposis-HHT germline mutation Methods sequenced DNA the AVM using targeted gene sequencing panel to at least 1000X identify might contribute development AVM. analysed whole genome SNP genotyping data algorithm Mosaic Chromosomal Alterations (MoChA) loss heterozygosity. Results confirmed (c.1610A>T, p.Asp537Val) identified second-hit also (c.350dup, p.Tyr117*) occurred trans relative mutation. heterozygosity on q arm chromosome 18, including Additionally, causes wild-type allele. Thus, two independent alterations causing function tissue. Conclusion AVM, evidence follows pathogenesis.

Language: Английский

Citations

1
BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance DOI

Teresa L. Capasso,

Bijun Li,

Harry J. Volek

et al.

Angiogenesis, Journal Year: 2019, Volume and Issue: 23(2), P. 203 - 220

Published: Dec. 11, 2019

Language: Английский

Citations

68
Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia DOI Open Access
Claire L. Shovlin, Ilenia Simeoni, Kate Downes

et al.

Blood, Journal Year: 2020, Volume and Issue: 136(17), P. 1907 - 1918

Published: June 23, 2020

Language: Английский

Citations

59
Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling DOI Creative Commons
Simon Tual‐Chalot,

Maria Garcia-Collado,

Rachael Redgrave

et al.

Circulation Research, Journal Year: 2019, Volume and Issue: 126(2), P. 243 - 257

Published: Dec. 6, 2019

ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and strongly expressed in endothelial cells. Mutations lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases larger arteriovenous malformations (AVMs); but how functions regulate adult vasculature not understood.The goal of work was determine maintains vessel caliber life prevent AVM formation thereby protect heart function.Genetic depletion Eng mice led significant reduction mean aortic blood pressure. There no evidence hemorrhage, anemia, or AVMs major organs explain reduced However, large developed peripheral intimately associated with pelvic cartilaginous symphysis-a noncapsulated cartilage naturally high endogenous expression VEGF (vascular growth factor). The increased flow through these explained drop pressure cardiac preload, stroke volumes, ultimately resulting high-output failure. Development this region occurred because loss cells leads sensitivity hyperproliferative response. progression failure absence attenuated targeting signaling an anti-VEGFR2 (VEGF receptor 2) antibody.ENG promotes normal balance quiescent maintain caliber-an essential function conditions such as hypoxia inflammation. In ENG, drives abnormal proliferation regions expression, leading rapid injurious impact on function.

Language: Английский

Citations

57