• Arteriovenous differentiation
• Protein acetylation
• Smad1/5 signalling

• Animals
• Smad5 Protein/metabolism
• Smad5 Protein/genetics
• Smad1 Protein/metabolism
• Smad1 Protein/genetics
• Acetylation
• Gene Expression Regulation, Developmental
• Receptor, Notch1/metabolism
• Receptor, Notch1/genetics
• Mice, Knockout
• Regional Blood Flow
• Signal Transduction
• Aorta/metabolism
• Aorta/physiopathology
• Aorta/embryology
• Receptor, Transforming Growth Factor-beta Type I/metabolism
• Receptor, Transforming Growth Factor-beta Type I/genetics
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Protein Processing, Post-Translational
• Transforming Growth Factor beta1/metabolism
• Transforming Growth Factor beta1/genetics
• Mice, Inbred C57BL
• Receptors, Transforming Growth Factor beta/metabolism
• Receptors, Transforming Growth Factor beta/genetics
• Mice
• Sodium-Calcium Exchanger

• G091018N Fonds Wetenschappelijk Onderzoek
• C14/19/095 KU Leuven

• Angiogenesis
• Arteriovenous malformations
• Cell volume
• Oxygen-induced retinopathy

• Animals
• Arteriovenous Malformations/genetics
• Arteriovenous Malformations/metabolism
• Arteriovenous Malformations/pathology
• Arteriovenous Malformations/physiopathology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Signal Transduction
• Cell Movement
• Disease Models, Animal
• TOR Serine-Threonine Kinases/metabolism
• Activin Receptors, Type I/genetics
• Activin Receptors, Type I/metabolism
• Mice, Inbred C57BL
• Cell Size
• Retinal Artery/metabolism
• Retinal Artery/pathology
• Retinal Artery/physiopathology
• Cell Proliferation
• MTOR Inhibitors/pharmacology
• Retinal Vessels/metabolism
• Retinal Vessels/pathology
• Retinal Vessels/physiopathology
• Retinal Vein/pathology
• Phenotype
• Oxygen/metabolism
• Retinal Neovascularization/genetics
• Retinal Neovascularization/metabolism
• Retinal Neovascularization/pathology
• Retinal Neovascularization/prevention & control
• Retinal Neovascularization/physiopathology
• Activin Receptors, Type II

• 17CVD03 Fondation LeDucq
• 801423 European Commission
• LCF/PR/HR22/52420027 La Caixa Foundation
• 842498 EU MSCA
• 679368 European Research Council
• 17CVD03 Fondation Leducq
• LCF/PR/HR22/52420027 'la Caixa' Foundation

• RASA1
• RASopathies
• capillary malformation
• capillary malformation‐arteriovenous malformation syndrome

• Adolescent
• Adult
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Capillaries/abnormalities
• Capillaries/pathology
• Facies
• Genetic Predisposition to Disease
• Germ-Line Mutation/genetics
• p120 GTPase Activating Protein/genetics
• Pedigree
• Phenotype
• Port-Wine Stain/genetics
• Port-Wine Stain/pathology
• Arteriovenous Malformations/genetics

• VEGF
• angiogenesis
• hereditary haemorrhagic telangiectasia
• liver transplantation
• vascular malformation

• Humans
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Liver Transplantation
• Angiogenesis Inhibitors/therapeutic use
• Liver/blood supply
• Signal Transduction
• Hypertension, Portal/etiology
• Hypertension, Portal/physiopathology
• Bevacizumab/therapeutic use

• Humans
• Female
• Male
• Pulmonary Artery/abnormalities
• Pulmonary Artery/diagnostic imaging
• Pulmonary Artery/physiopathology
• Retrospective Studies
• Embolization, Therapeutic/adverse effects
• Middle Aged
• Recurrence
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/diagnostic imaging
• Hypertension, Pulmonary/physiopathology
• Hypertension, Pulmonary/therapy
• Treatment Outcome
• Pulmonary Veins/abnormalities
• Pulmonary Veins/diagnostic imaging
• Pulmonary Veins/physiopathology
• Adult
• Arteriovenous Malformations/therapy
• Arteriovenous Malformations/diagnostic imaging
• Arteriovenous Malformations/complications
• Risk Factors
• Time Factors
• Aged
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnostic imaging
• Telangiectasia, Hereditary Hemorrhagic/therapy
• Young Adult
• Arterial Pressure

• Humans
• Telangiectasia, Hereditary Hemorrhagic/drug therapy
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Arteriovenous Malformations/metabolism
• Signal Transduction/genetics

• Genetics
• Hereditary hemorrhagic telangiectasia
• Hypoxia
• Rare diseases
• SMAD6

• Humans
• Endothelial Cells/pathology
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/pathology
• Mutation
• Genetic Testing
• Endoglin/genetics
• Activin Receptors, Type II/genetics

• AVM
• CMAVM
• HHT
• children

• Child
• Humans
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Telangiectasia, Hereditary Hemorrhagic/epidemiology
• Prevalence
• Retrospective Studies
• Epistaxis
• Intracranial Arteriovenous Malformations/complications
• Intracranial Arteriovenous Malformations/epidemiology
• Arteriovenous Fistula/complications
• Arteriovenous Fistula/epidemiology

• chronic thromboembolic pulmonary hypertension
• hereditary hemorrhagic telangiectasia
• high‐output heart failure
• pulmonary arterial hypertension
• pulmonary hypertension

• ALK1—Activin receptor-like kinase 1
• AVM—Arteriovenous Malformation
• BMP—Bone Morphogenic Protein
• ENG—Endoglin
• Epistaxis
• HHT—Hereditary Haemorrhagic Telangiectasia

• Humans
• Activin Receptors, Type II/genetics
• Arteriovenous Malformations/genetics
• Arteriovenous Malformations/pathology
• Bone Morphogenetic Proteins/genetics
• Mutation
• Signal Transduction
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/therapy

• R01 HL164891 NHLBI NIH HHS

Hereditary hemorrhagic teleangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is the most common cause of hepatic vascular malformations in adults. Different vascular shunts (arteriovenous, arterioportal or portovenous) lead to different clinical manifestations. Even though no hepatic-related symptoms are reported in the majority of cases, the severity of liver disease could lead to refractory medical conditions, in some cases requiring liver transplantation. The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.

• Hereditary hemorrhagic teleangiectasia
• Rendu-Osler-Weber syndrome
• Hepatic vascular malformations
• Liver

• arteriovenous malformations
• next-generation sequencing
• somatic mosaicism

• angiogenesis
• endoglin
• endothelial cell
• hereditary hemorrhagic telangiectasia
• microRNA

• Humans
• Endoglin/genetics
• Human Umbilical Vein Endothelial Cells/metabolism
• MicroRNAs/genetics
• Signal Transduction
• Telangiectasia, Hereditary Hemorrhagic/genetics

• U54 NS065705 NINDS NIH HHS
• U54 NS065705 NIH HHS

• Hereditary hemorrhagic telangiectasia
• anemia
• bleeding
• bone morphogenetic protein
• missense mutation
• whole-exome sequencing

• ALK1
• AVM
• BMP
• ENG
• HHT
• SMAD4
• endothelial cells

Hereditary hemorrhagic telangiectasia is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. As complications, it presents vascular malformations in organs such as the lung, liver, digestive tract, and brain. Currently, diagnosis can be made using the Curaçao criteria or by identifying the affected gene. In recent years, there has been an advance in the understanding of the pathophysiology of the disease, which has allowed the use of new therapeutic strategies to improve the quality of life of patients. This article reviews some of the main and most current evidence on the pathophysiology, clinical manifestations, diagnostic approach, screening for complications, and therapeutic options, both pharmacological and surgical.

• VEGF
• angiogenesis
• arteriovenous malformations
• epistaxis
• hereditary hemorrhagic telangiectasias
• telangiectasias

• genetic testing
• somatic mosaicism
• vascular malformations
• vascular tumors

To discuss the clinical features of a patient with hereditary hemorrhagic telangiectasia (HHT).

The clinical data of one patient with HHT are retrospectively analysed. In addition, we review the relevant literature.

A 32‐year‐old male patient was admitted to the hematology outpatient department of our hospital and presented with intermittent epistaxis for 24 years. In recent years, he was diagnosed with iron deficiency anemia. The nasal endoscopic examination showed telangiectasia at the front of the right‐middle turbinate and the left nasal cavity. He had ENG genetic mutation positivity.

Patients with HHT may suffer from many complications, including bleeding, anemia, iron deficiency, and high‐output heart failure. These patients may have telangiectasias and arteriovenous malformations in various organs.

• anemia
• hemorrhage
• telangiectasia

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant vascular disease defined by the presence of mucosal and cutaneous telangiectasia and visceral arterio-venous malformations. The latter are abnormal capillary-free direct communications between the pulmonary and systemic circulations with the following consequences: arterial hypoxemia caused by right-to-left shunts; paradoxical embolism with transient ischemic attack or stroke and brain abscess caused by the absence of the normally filtering capillary bed; and hemoptysis or hemothorax due to the rupture of the thin-walled arterio-venous malformations (particularly during pregnancy). It is frequently underdiagnosed, commonly presenting as complications from shunting through arterio-venous malformations: dyspnea, chronic bleeding, or embolism. Arterio-venous malformations are present not only in the lungs, but can also be found in the liver, central nervous system (mainly in the brain), nasal mucosa, or the gastrointestinal tract. The first choice of therapy is embolization of the afferent arteries of the arterio-venous malformations, a minimally invasive procedure with a high efficacy, a low morbidity, and low mortality. Other therapeutic modalities are surgery (resection) or stereotactic radiosurgery (using radiation). Routine screening for arterio-venous malformations is indicated in patients diagnosed with this condition and can prevent severe complications such as acute hemorrhages, brain abscesses, or strokes. Clinicians should provide a long-term follow-up for patients with arterio-venous malformations, in an effort to detect their growth or reperfusion in case of previously treated malformations. In spite of two experts’ consensuses, it still possesses multiple therapeutic challenges for physicians, as several aspects regarding the screening and management of arterio-venous malformations still remain controversial. Multidisciplinary teams are especially useful in complex cases.

Background. Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant genetic disorder characterized by life-threatening vascular dysplasia. Myeloid angiogenic cells (MACs), alternatively called early endothelial progenitor cells or circulating angiogenic cells, do not directly incorporate into developing blood vessels, but augment angiogenesis in a paracrine manner. MAC dysfunction has been reported in HHT. MicroRNAs (miRNAs) regulate cellular function by modulating gene expression post-transcriptionally. To date, the role of miRNAs in HHT MAC dysfunction has not been documented. Objective. The goal of this study was to comparatively profile miRNAs in HHT patient and control MACs to identify dysregulated miRNAs that may be responsible for the observed MAC dysfunction in HHT. Methodology/Results. Twenty-three dysregulated miRNAs (twenty-one upregulated and two downregulated) in HHT MACs were identified with a TaqMan miRNA microarray. Pathway enrichment analysis showed that the dysregulated miRNAs were significantly enriched in pathways involved in HHT pathogenesis, such as the transforming growth factor β (TGFβ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Hippo signalling pathways. Furthermore, miR-132-3p was determined to be significantly reduced in HHT MACs compared with controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis revealed that miR-132-3p is significantly enriched in the TGFβ and PI3K/AKT signalling pathways, targeting SMAD4, an effector of the TGFβ signalling pathway and RASA1, a negative regulator of the PI3K/AKT signalling pathway, respectively. Conclusion. MiRNA dysregulation, specifically reduced expression of miR-132-3p, in HHT MACs was identified. The dysregulated miRNAs are significantly enriched in the TGFβ, PI3K/AKT, and Hippo signalling pathways. These data suggest that alteration in miRNA expression may impair these pathways and contribute to MAC dysfunction in HHT.

• Adolescent
• Anemia/complications
• Anemia/diagnosis
• Anemia/therapy
• Disease Management
• Epistaxis/complications
• Epistaxis/diagnosis
• Epistaxis/therapy
• Female
• Gastrointestinal Hemorrhage/complications
• Gastrointestinal Hemorrhage/diagnosis
• Gastrointestinal Hemorrhage/therapy
• Humans
• Pregnancy
• Pregnancy Complications, Hematologic/diagnosis
• Pregnancy Complications, Hematologic/therapy
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Telangiectasia, Hereditary Hemorrhagic/therapy

• epistaxis
• hereditary hemorrhagic telangiectasia

• Epistaxis
• Humans
• Telangiectasia, Hereditary Hemorrhagic/genetics

• GDF2
• HHT5
• hereditary hemorrhagic telangiectasia

• endoglin
• hereditary hemorrhagic telangiectasia
• vegf receptor 2
• primary human endothelial cells
• angiogenesis
• erk
• akt
• cell migration
• cell apoptosis

• genetic testing
• hereditary hemorrhagic telangiectasia
• interventional radiology
• vascular anomalies

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.

• BMP
• BMP pathway fine-tuning
• lymphatic vessel biology
• mechano-transduction
• signaling cross-talk
• vascular malformations

A founder effect can result from the establishment of a new population by individuals from a larger population or bottleneck events. Certain alleles may be found at much higher frequencies because of genetic drift immediately after the founder event. We provide a systematic literature review of the sporadically reported founder effects in hereditary hemorrhagic telangiectasia (HHT). All publications from the ACVRL1, ENG and SMAD4 Mutation Databases and publications searched for terms “hereditary hemorrhagic telangiectasia” and “founder” in PubMed and Scopus, respectively, were extracted. Following duplicate removal, 141 publications were searched for the terms “founder” and “founding” and the etymon “ancest”. Finally, 67 publications between 1992 and 2020 were reviewed. Founder effects were graded upon shared area of ancestry/residence, shared core haplotypes, genealogy and prevalence. Twenty-six ACVRL1 and 12 ENG variants with a potential founder effect were identified. The bigger the cluster of families with a founder mutation, the more remarkable is its influence to the populational ACVRL1/ENG ratio, affecting HHT phenotype. Being aware of founder effects might simplify the diagnosis of HHT by establishing local genetic algorithms. Families sharing a common core haplotype might serve as a basis to study potential second-hits in the etiology of HHT.

• founder effect
• genealogy
• germline mutation
• haplotype
• hereditary hemorrhagic telangiectasia
• population genetics

• HHT pathogenic variant
• Osler-Weber-Rendu syndrome
• arteriovenous malformation
• genetic testing
• hereditary hemorrhagic telangiectasia

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing “bleeding disorders databases”, which are excellent supports for clinical patient management.

• APTT prolongation
• differential diagnosis
• hemophilia A
• hereditary hemorrhagic telangiectasia
• next generation sequencing
• prekallikrein deficiency
• rare bleeding disorders
• von Willebrand disease

• Angiogenesis
• Arteriovenous malformations
• De novo mutation
• Mosaicism
• Somatic
• Vascular biology

• arterial malformation
• arteriovenous malformation
• capillary malformation
• lymphatic malformation
• vascular malformation
• venous malformation

• Atherosclerosis
• Bone morphogenetic protein
• Chronic kidney disease
• Diabetes
• Medial calcification
• Mineralization
• Transforming growth factor beta
• Vascular calcification
• Vascular disease

• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 4
• Bone Morphogenetic Protein 7
• Bone Morphogenetic Proteins/metabolism
• Carrier Proteins
• Humans
• Signal Transduction
• Vascular Calcification

• R01 AR057374 NIAMS NIH HHS
• R01 HL131910 NHLBI NIH HHS
• R42 HL132742 NHLBI NIH HHS
• UG3 TR002617 NCATS NIH HHS

Ras p21 protein activator 1 (RASA1) is a regulator of Ras GDP and GTP and is involved in numerous physiological processes such as angiogenesis, cell proliferation, and apoptosis. As a result, RASA1 also contributes to pathological processes in vascular diseases and tumour formation. This review focuses on the role of RASA1 in multiple tumours types in the lung, intestines, liver, and breast. Furthermore, we discuss the potential mechanisms of RASA1 and its downstream effects through Ras/RAF/MEK/ERK or Ras/PI3K/AKT signalling. Moreover, miRNAs are capable of regulating RASA1 and could be a novel targeted treatment strategy for tumours.

• cardiovascular medicine
• clinical genetics

• BMP9
• GDF2
• hereditary hemorrhagic telangiectasia
• lymphatic dysplasia
• nonimmune hydrops fetalis
• pulmonary arterial hypertension

• BMP10
• BMP9
• GDF2
• pulmonary arterial hypertension

Considering the predominant role of rare variants of the Bone morphogenetic protein 9 (BMP9) gene in the occurrence of idiopathic pulmonary arterial hypertension (IPAH), here we conducted a case-control study, together with functional validation, to explore the relationships between variants of the BMP9 gene and development of IPAH. We found minor alleles of rs3740297 (OR: 0.72, 95% CI: 0.59-0.87, P=7.77×10-5) and rs7923671 (OR: 0.76, 95% CI: 0.62-0.93, P=0.009) were significantly associated with decreased risk of IPAH. Minor alleles of rs3740297 and rs7923671 were significantly associated with increased plasma level of BMP9 in both IPAH cases and controls (P<0.001). An allele of rs7923671 showed higher relative luciferase activity compared to that containing G allele (P<0.001). Mechanism exploration found that pulmonary artery smooth muscle cells (PASMC) cell line transfected with rs3740297 C allele construct, miR-149 mimic, and antagomir miR-149 showed more sensitive change of the relative luciferase activity and BMP9 expression. This means minor allele T of rs3740297 could significantly decrease susceptibility of IPAH in Chinese population, possibly by increasing BMP9 expression through losing a miR-149 binding site. Our study provides evidence for genetic associations between two specific variants in the BMP9 gene and plasma level of BMP9, occurrence of IPAH.

• BMP9
• biomarker
• polymorphism
• pulmonary arterial hypertension

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

• ALK1
• Bevacizumab
• Bone morphogenetic protein signaling
• Drug repositioning
• Hereditary hemorrhagic telangiectasia
• High throughput screening
• Tacrolimus
• Vascular malformations

• Vein of Galen malformation
• arteriovenous malformation
• cerebrovascular disorders
• ephrin signaling
• neurosurgery
• vasculogenesis

• CM-AVM
• EPHB4
• HHT
• capillary malformation
• telangiectasia

• Ortner syndrome
• Pulmonary arterial hypertension
• hereditary haemorrhagic telangiectasia type 2
• veno-arterial extracorporeal membrane oxygenation