Hereditary Hemorrhagic Telangiectasia Research Articles

Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptors ACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression of Acvrl1 prevents AVM development in both Acvrl1 and Eng null mice, enhancing ACVRL1 expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism of ACVRL1 regulation. We previously demonstrated in zebrafish embryos that acvrl1 is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and that acvrl1 expression is rapidly restored after reinitiation of flow. Furthermore, we find that acvrl1 expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that, in the absence of flow, intravascular injection of BMP10 or the related ligand, BMP9, restores acvrl1 expression in an Alk1-dependent manner. Using a transgenic acvrl1:egfp reporter line, we find that flow and Bmp10 regulate acvrl1 at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases in ACVRL1 in human endothelial cells subjected to shear stress. These data suggest that ligand-dependent Alk1 activity acts downstream of blood flow to maintain or enhance acvrl1 expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux and ACVRL1 expression.

May 2024 Medical Image of the Month: Hereditary Hemorrhagic Telangiectasia in a Patient on Veno-Arterial Extra-Corporeal Membrane Oxygenation

No abstract available. Manuscript truncated after 150 words. A 54-year-old man with a complex cardiac history, including Tetralogy of Fallot requiring Blalock-Taussig shunt in infancy, infundibular patch repair at age 7, and bioprosthetic tricuspid valve replacement at age 52, had ongoing frequent hospitalizations with decompensated right ventricular heart failure secondary to native pulmonary valve mixed stenosis plus regurgitation and left pulmonary artery stenosis. His case was further complicated by his history of hereditary hemorrhagic telangiectasia (HHT) with recurrent epistaxis and recent GI bleeds with multiple angiodysplastic lesions throughout the stomach, duodenum, and descending colon which were previously treated with argon plasma coagulation. The patient was admitted to our hospital in NYHA class IV heart failure receiving a continuous dopamine infusion and aggressive diuresis. Upon admission, a right heart catheterization demonstrated severe pulmonary valve regurgitation, left pulmonary artery stenosis, and systemic hypoxemia suggestive of an intrapulmonary shunt. Admission transthoracic echocardiogram demonstrated normal left ventricular ejection fraction of 55-60%, a …

Hereditary Hemorrhagic Telangiectasia - a literature review

Introduction and purpose: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and complex vascular disorder characterized by abnormal blood vessel formation. It can present significant challenges in diagnosis and management, as it is currently estimated up to 90% of those affected are never diagnosed. Despite its rarity, HHT can carry substantial implications for patients and their families, at times requiring comprehensive medical care and support. This paper aims to provide an in-depth exploration of HHT, encompassing its epidemiology, genetics, clinical manifestations, diagnostic approaches, and current management strategies. Moreover, we hope to point out possible areas in need of future research.
 Description of the state knowledge: HHT is an autosomal dominant genetic disorder that affects 1 in 5-10,000 people. Its most prominent symptoms include telangiectasia of skin and mucous membranes, recurrent epistaxis, gastrointestinal bleeding and arteriovenous malformations in vital organs. In the vast majority of cases, it is caused by a mutation in one of the following genes: ENG, ACVRL1, SMAD4; however, mutations in other genes have been described to cause a similar or much the same constellation of symptoms. Treatment options are focused on managing symptoms and improving quality of life, but possible new treatment options are being researched that could change the landscape of HHT management.
 Summary: HHT is a severely underdiagnosed disease that has seen a surge of researchers’ interest in recent years. We firmly believe that, combined with plummeting costs of genetic testing and possible new treatment options, means that HHT will become increasingly important in physicians’ everyday practice.

Hereditary hemorrhagic telangiectasia may be the most morbid inherited bleeding disorder in women

AbstractHereditary hemorrhagic telangiectasia (HHT) is the second-most common inherited bleeding disorder (BD) worldwide and remains without approved therapies. HHT causes serious mucosal bleeding resulting, in severe iron-deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in the brain, lung, and liver, which can cause life-threatening hemorrhagic complications. No study has examined the relative morbidity of HHT and von Willebrand disease (VWD), which is the most common inherited BD in women. We performed an observational cohort study of women with HHT or VWD, comparing a representative sample of 100 randomly selected women with HHT to 100 randomly selected age-matched women with VWD. In HHT vs VWD, recurrent epistaxis and gastrointestinal bleeding were more likely (odds ratio [OR], 32.73 [95% confidence interval, 13.81-71.80]; P < .0001 and 5.69 [2.59-12.89]; P < .0001) and heavy menstrual bleeding was less likely (OR, 0.32 [0.18-0.57]; P < .0001). Iron-deficiency anemia was significantly more likely, and the lowest hemoglobin was significantly lower in HHT than in VWD. The odds of iron infusion dependence, requirement for red cell transfusion, and hemostatic surgical procedures were significantly higher—17-fold, threefold, and eightfold higher, respectively—and hospital admissions to manage disease complications were both ∼14 times more frequent in women with HHT vs those with VWD. In conclusion, much higher disease-related morbidity, mortality, and health care use were observed in women with HHT vs VWD, providing evidence that HHT may be the most clinically significant inherited BD in women. Given the vast gap in research funding for HHT compared with both hemophilia (a disease primarily of men) and VWD, these findings have significant implications for gender equity in hematology.

Phenotypic characterisation of SMAD4 variant carriers

BackgroundBoth hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective...

Clinical and morphological features of Osler-Weber-Randu disease with signs of visceral injury

Randu-Osler-Weber disease or hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by dilated capillaries and veins, which are usually localized on the skin and mucous membranes of the oral cavity, as well as in the respiratory, urinary and digestive tracts. The anatomical basis of the disease is damage to blood vessels with degeneration and hypoplasia of the muscle and elastic layers, resulting in focal thinning of the vessel walls with further expansion of their lumen. Violation of angiogenesis persists throughout the patient's life, and is manifested by the formation of aneurysms, telangiectasias, and arteriovenous shunts. The average life expectancy of patients with burdened heredity is 63.2 years. The peak of mortality occurs at the age of 50, which is mainly associated with acute complications of the disease. However, among people suffering from Randu-Osler-Weber disease there are also long-lived people who die at the age of 70-79 years, and the cause of death is the complication of the main disease and the addition of chronic diseases. The purpose of this article is to consider in more detail possible manifestations and complications, methods of treatment of Randu-Osler-Weber disease for timely recognition of the disease and provision of timely medical assistance. This article describes a case of an abdominal form of hereditary hemorrhagic telangiectasia in an 82-year-old patient. The results of the postmortem pathomorphological examination of damaged tissues due to Randu-Osler-Weber disease are presented. During the study of micropreparations of the mucous lip, small intestine, mesentery of the small intestine and liver, groups of vessels were found, the wall of which is thinned in places and thickened in places, in the wall of these vessels there is a decrease or complete absence of muscle and elastic fibers, only endothelium is present, surrounded by loose connective tissue, postcapillary venules expand and anastomose with arterioles. In the lumen of these falsely developed vessels, mixed thrombi are determined. An elderly patient suffered from a combined pathology: hereditary hemorrhagic telangiectasia with arterio-venous malformations in the liver, heart, mesentery, small intestine, and coronary heart disease. These processes were complicated by the development of congestive heart failure, which disturbed the hemodynamic and rheological properties of blood and contributed to the occurrence of thrombosis of arterio-venous malformations in the mesentery and the wall of the small intestine. In the following, necrosis of the loops of the small intestine occurred with the development of diffuse purulent-fibrinous peritonitis and endogenous intoxication. Patients with hereditary hemorrhagic telangiectasia have a higher risk of bleeding and neurological complications, including anemia, cerebral abscess, stroke, venous thrombosis, and heart failure, because of late diagnosis of this hereditary disease. Early diagnosis is based on clinical data and careful collection of family history. In 90% of patients under the age of 40, the diagnosis of hereditary hemorrhagic telangiectasia can be established using the Curaçao criteria. This disease brings a significant amount of suffering in everyday life for both patients and their families, and requires significant attention of a multidisciplinary team of doctors at every stage of medical care.

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia

AbstractNo US Food and Drug Administration– or EMA-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti–vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

Pediatric Lung Transplantations: New Possibilities and Challenges in Treatment of Children With End-Stage Respiratory Failure

Lung transplantation (LTx) is the last treatment option for children with end-stage respiratory failure. According to the literature, cystic fibrosis remains the most common cause of pediatric LTx. The study aimed to assess the characteristics of pediatric LTx recipients as well as the outcomes of the transplantation. Our study is a single-center retrospective review of clinical data of all 11 patients who underwent a LTx before the age of 18 years between the years 2016 and 2020. Medical records were examined for patients' characteristics, general treatment, and complications. There were a total of 11 patients (8 males) with a median age 14.5 years (range: 11-17). The primary diseases that led to LTx were: cystic fibrosis in 8 patients (72.73%), hereditary hemorrhagic telangiectasia in 2 patients (18.18%), and idiopathic pulmonary arterial hypertension in 1 patient (9.09%). Median period from qualification to LTx was 235.55 days (range: 11-748). Two patients (18.18%) underwent lung retransplantation after 3 and 5 years. One patient passed away 10 months after surgery due to noncompliance. Pediatric lung transplantation is less common than lung transplantation in adults. It also differs in fields of donors accessibility, stronger immune system response and noncompliance that may lead to graft failure.

Survival rate and death risk for associated pulmonary arterial hypertension: A retrospective population-based study

Purpose: This study aimed to assess the survival rate (SR) and death risk for associated pulmonary arterial hypertension (aPAH; 10th revision of the International Statistical Classification of Diseases [ICD-10], I27.2) in Koreans.Methods: The data were collected from the Korean National Health Insurance Service from 2006 through 2017 (n= 15,448). We analyzed the SR using the Kaplan-Meier method and carried out Cox proportional hazards analyses.Results: Patients’ mean age upon aPAH diagnosis was 60.1±24.0 years, and 60.7% of the patients were female. The 10-year SR of aPAH was 46.3% (95% confidence interval, 45.0 to 47.6). The factors associated with an increase in the adjusted death risk included age of 0 to 9 years, advancing age, male sex, lower income level, and comorbidities including diabetes mellitus, myocardial infarction, heart failure, hemorrhagic stroke, chronic kidney disease, malignant neoplasm, hereditary hemorrhagic telangiectasia, and systemic lupus erythematosus.Conclusion: The 10-year SR of aPAH was over 46%. The risk of death from aPAH was significantly higher with advancing age, sex, lower income level, and comorbidities.

Brain AVM compactness score in children with hereditary hemorrhagic telangiectasia.

The brain arteriovenous malformation (BAVM) nidus compactness score (CS), determined on angiography, predicts BAVM recurrence after surgical resection among children with sporadic BAVMs. We measured theangiographic CS for BAVMs among children with hereditary hemorrhagic telangiectasia (HHT) to determine CS characteristics in this population. A pediatric interventional neuroradiologist reviewed angiograms to determine the CS of BAVMs in children with HHT recruited to the BVMC. CS is based on overall nidus and perinidal anomalous vessel compactness. CS categories included 1 = diffuse nidus, 2 = intermediate nidus, and 3 = compact nidus. Forty-eight of 78 children (61.5%) with HHT and brain vascular malformations had a conventional angiogram; 47 (97.9%) angiograms were available. Fifty-four BAVMs were identified in 40 of these 47 children (85.1%). Of 54 BAVMs in children with HHT, CS was 1 in 7 (13%), 2 in 29 (53.7%), and 3 in 18 BAVMs (33.3%) compared with CS of 1 in six (26.1%), 2 in 15 (65.2%), and 3 in 2 BAVMs (8.7%) among 23 previously reported children with sporadic BAVMs, p = 0.045 (Fisher's exact). Seven children with HHT had intracranial hemorrhage: 4 had CS = 3, 1 had CS = 2, and 2 had CS = 1. A range of CSs exists across HHT BAVMs, suggesting it may be an angiographic measure of interest for future studies of BAVM recurrence and hemorrhage risk. Children with HHT may have more compact niduses compared to children with sporadic BAVMs. Additional research should determine whether CS affects hemorrhage risk or post-surgical recurrence risk in HHT-associated BAVMs, which could be used to direct BAVM treatment.

Telangiectasias, recurrent epistaxis and a strong family history—a case of Osler-Weber-Rendu Syndrome in Pakistan

Osler-Weber-Rendu syndrome or Hereditary Haemorrhagic Telangiectasia (HHT) is a rare condition, with very few reported cases, especially in Pakistan. As healthcare workers, we encounter multiple cases of recurrent epistaxis in the emergency as well as out-patient departments. However, patients are usually treated symptomatically without a thorough workup. HHT should be considered among the differentials for recurrent epistaxis, as a clinical diagnosis can be made with detailed family history and physical examination. Here is the case of a 58-year-old male who presented to the Gastroenterology OPD, Combined Military Hospital, Lahore, in November 2021, with complaints of generalised weakness and blood in stools. He had a history of recurrent epistaxis and telangiectasias, and further inquiry revealed a strong family history of similar symptoms. He was diagnosed as a case of Osler-Weber-Rendu Syndrome. Informed consent was taken from the patient prior to the writing of the manuscript.

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT

AbstractFor monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 prephenotyped patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.

BMP9 is a key player in endothelial identity and its loss is sufficient to induce arteriovenous malformations.

BMP9 is a high affinity ligand of ALK1 and endoglin receptors that are mutated in the rare genetic vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT). We have previously shown that loss of Bmp9 in the 129/Ola genetic background leads to spontaneous liver fibrosis via capillarization of liver sinusoidal endothelial cells (LSEC) and kidney lesions. We aimed to decipher the molecular mechanisms downstream of BMP9 to better characterize its role in vascular homeostasis in different organs. For this, we performed a RNAseq analysis on LSEC from adult WT and Bmp9-KO mice and identified over 2000 differentially expressed genes. Gene ontology analysis showed that Bmp9 deletion led to a decrease in BMP and Notch signaling, but also LSEC capillary identity while increasing their cell cycle. The gene ontology term "glomerulus development" was also negatively enriched in Bmp9-KO mice versus WT supporting a role for BMP9 in kidney vascularization. Through different imaging approaches (electron microscopy, immunostainings), we found that loss of Bmp9 led to vascular enlargement of the glomeruli capillaries associated with alteration of podocytes. Importantly, we also showed for the first time that the loss of Bmp9 led to spontaneous arteriovenous malformations (AVMs) in the liver, gastro-intestinal tract and uterus. Altogether, these results demonstrate that BMP9 plays an important role in vascular quiescence both locally in the liver by regulating endothelial capillary differentiation markers and cell cycle but also at distance in many organs via its presence in the circulation. It also reveals that loss of Bmp9 is sufficient to induce spontaneous AVMs, supporting a key role for BMP9 in the pathogenesis of HHT.

Rare bleeding disorders: Advances in management

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Conservative management by embolization of a ruptured renal arterio-venous malformation (AVM) in Hereditary Hemorrhagic Telangiectasia (HHT)

BackgroundRenal arteriovenous malformation (AVM) in Hereditary Hemorrhagic Telangiectasia (HHT) is uncommon and only few cases have been described, mainly with surgical management because of uncontrolled hematuria.Case presentationWe managed a 70-year-old patient with HHT who presented with hematuria and left flank pain. Computed Tomography and ultrasound showed left renal AVM of 18 mm with clotting in the urinary tract. An external ureteral catheter was placed during 3 days to allow rinsing and facilitate elimination of clots.Given the patient's hemodynamic stability, a non-surgical management was chosen. Treatment of the AVM was performed by trans-arterial embolization using micro-coils and ethylene–vinyl alcohol copolymer.ConclusionsOur case study shows a conservative management by embolization of ruptured left renal AVM revealed by hematuria in a 70-year-old patient with HHT.

Hereditary hemorrhagic telangiectasia diagnosis: A case report

This case report presents a 13-year-old patient with a lung nodule identified on a chest radiograph in the emergency department during an evaluation of knee and side pain after a fall. The patient had nosebleeds, family history of hereditary hemorrhagic telangiectasia (HHT) and after chest computed tomography with angiography, the nodule was defined as a single pulmonary arteriovenous malformation (PAVM). Neither parent nor patient had been evaluated for HHT, an autosomal dominant disease, despite the family history. This patient satisfied the clinical criteria for the diagnosis and had a confirmatory genetic test, which led to diagnosis in mother also. The patient's PAVMs were treated, decreasing the risk of life threatening complications. Diagnosing HHT in children is often delayed or missed, even in families with HHT, as in this case report. Without any physical signs or clinical symptoms, families and healthcare providers often dismiss the possibility of the diagnosis. Children with HHT are at the same risk for complications of stroke, anemia, hypoxemia, heart failure and increased morbidity as adults. It is essential to recognize the importance of family history when evaluating children in primary care and urgent settings, as this patient's diagnosis was delayed 13 years. Awareness of HHT signs and symptoms are essential to early referral to an HHT specialist, for diagnosis and management.

Surgery or No Surgery? Exploring the Dilemma of Epistaxis Management in Patients with HHT.

Background: Epistaxis, particularly in Hereditary Hemorrhagic Telangiectasia (HHT) patients, is a common otolaryngological emergency, often requiring complex management. A hierarchy of increasingly invasive interventions, from external compression of the nasal pyramid to nostril closure, is typically proposed and applied. Methods: We conducted a retrospective study on HHT patients to assess the effectiveness and longevity of invasive procedures postoperatively. Data were collected using the Epistaxis Severity Score (ESS) questionnaire. The primary focus was on changes in the frequency and intensity of epistaxis, while the secondary focus was on the overall quality of life. Results: This study found that invasive procedures initially improved the frequency and intensity of epistaxis in HHT patients. However, within 1 to 9 months postoperatively, these benefits often diminished, with hemorrhagic symptoms recurring at similar or worsened levels. Conclusions: The findings suggest a need for a cautious and restrained approach to using invasive treatments in managing epistaxis in HHT patients. Highly invasive procedures should be reserved for cases where less invasive methods fail, due to their temporary effectiveness and the risk of causing anatomical-functional changes in the rhino-sinus area, complicating future management of severe epistaxis.

Hereditary hemorrhagic telangiectasia with hepatic arteriovenous shunt diagnosed due to liver damage.

A 53-year-old woman was diagnosed with liver dysfunction in August 20XX. Computed tomography (CT) revealed multiple hepatic AV shunts, and she was placed under observation. In March 20XX + 3, she developed back pain, and CT performed during an emergency hospital visit showed evidence of intrahepatic bile duct dilatation. She was referred to our gastroenterology department in May 20XX + 3. We conducted investigations on suspicion of hereditary hemorrhagic telangiectasia (HHT) with hepatic AV shunting based on contrast-enhanced CT performed at another hospital. HHT is generally discovered due to epistaxis, but there are also cases where it is diagnosed during examination of liver damage.

Large-scale phosphoproteomics reveals activation of the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells

BackgroundBMP9 and BMP10 are two major regulators of vascular homeostasis. These two ligands bind with high affinity to the endothelial type I kinase receptor ALK1, together with a type II receptor, leading to the direct phosphorylation of the SMAD transcription factors. Apart from this canonical pathway, little is known. Interestingly, mutations in this signaling pathway have been identified in two rare cardiovascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.MethodsTo get an overview of the signaling pathways modulated by BMP9 and BMP10 stimulation in endothelial cells, we employed an unbiased phosphoproteomic-based strategy. Identified phosphosites were validated by western blot analysis and regulated targets by RT-qPCR. Cell cycle analysis was analyzed by flow cytometry.ResultsLarge-scale phosphoproteomics revealed that BMP9 and BMP10 treatment induced a very similar phosphoproteomic profile. These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway and demonstrated that this activation required the expression of the protein GADD45β. In turn, activated P38 phosphorylated the heat shock protein HSP27 and the endocytosis protein Eps15 (EGF receptor pathway substrate), and regulated the expression of specific genes (E-selectin, hyaluronan synthase 2 and cyclooxygenase 2). This study also highlighted the modulation in phosphorylation of proteins involved in transcriptional regulation (phosphorylation of the endothelial transcription factor ERG) and cell cycle inhibition (CDK4/6 pathway). Accordingly, we found that BMP10 induced a G1 cell cycle arrest and inhibited the mRNA expression of E2F2, cyclinD1 and cyclinA1.ConclusionsOverall, our phosphoproteomic screen identified numerous proteins whose phosphorylation state is impacted by BMP9 and BMP10 treatment, paving the way for a better understanding of the molecular mechanisms regulated by BMP signaling in vascular diseases.

De Novo Brain Vascular Malformations in Hereditary Hemorrhagic Telangiectasia

ObjectiveApproximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation or VM growth. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening. We aimed to confirm whether brain VMs can form de novo in patients with HHT. MethodsThe BVMC HHT project is a 17-center longitudinal study enrolling patients since 2010. We analyzed the database for de novo VMs defined as those detected 1) on follow-up neuroimaging in a patient without previous brain VMs or 2) in a location distinct from previously identified brain VMs and reported those in whom a de novo VM could be confirmed on central neuroimaging review. ResultOf 1909 patients enrolled, 409 (21%) had brain VMs. Seven patients were recorded as having de novo brain VMs, and imaging was available for central review in four. We confirmed that three (0.7% of individuals with brain VMs) had de novo brain VMs (2 capillary malformations, 1 brain arteriovenous malformation) with intervals of six, nine, and 13 years from initial imaging. Two with de novo brain VMs were <18 years. The fourth patient, a child, did not have a de novo brain VM but had a radiologically confirmed increase in size of an existing brain arteriovenous malformation. ConclusionBrain VMs can, albeit rarely, form de novo or grow in HHT patients. Given their potential risk of hemorrhage, regular rescreening in patients with HHT may be warranted.