Development Of Vascular Malformations Research Articles

Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such as hemorrhage. However, brain VM treatment-surgical resection, embolization, and/or radiosurgery-is not recommended for all patients due to the associated risks. Given the scarcity of data regarding HHT-related brain VM presentation and treatment trends in pediatric patients, we aim to describe the clinical presentations and the patterns of treatment of HHT-related brain VMs in a pediatric cohort, and compare pediatric trends to those of adults. Demographic and clinical data were analyzed in 114 pediatric patients with HHT-related brain VMs and compared with a cohort of 253 adult patients enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. Our data demonstrated that a higher proportion of pediatric patients with HHT-related brain VMs were symptomatic at presentation (p = 0.004). Moreover, a higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001) and seizure (p = 0.002) compared to adult patients. Surgical resection was the most common brain VM treatment modality in both children and adults. We conclude that pediatric patients may be more likely to present with symptoms and complications from brain VMs, supporting the case for screening for brain VMs in children with HHT.

Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation.

Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA-driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA-driven VMs.

Genotype-Phenotype Correlations in Children with HHT.

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype–phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype–phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0–18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype—defined as both pulmonary AVMs and brain VMs—was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype–phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.

Abstract TP584: Higher Prevalence of Congestive Heart Failure (CHF) in Hereditary Hemorrhagic Telangiectasia (HHT) Secondary to Anemia and Artero-venous Malformations (AVMs)

Introduction: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder with vascular anomalies of various organ systems including the skin, brain, heart, lungs, and liver. While the most commonly recognized disease burden of HHT are epistaxis and mucocutaneous telangiectasia, the development of vascular malformations can result in more severe symptoms such as cerebral hemorrhage, liver cirrhosis, and stroke. Various case reports/series have reported high output cardiac failure, secondary to presence of a single large AVM or multi organ AVMs, as a major cause of morbidity and mortality in HHT population. To the best of our knowledge, this is the first study analyzing the cardiovascular disease burden in HHT patients from a large national database. Methodology: All HHT patients were identified using ICD-9 code 448.0 using the 2014 National Inpatient Sample (NIS) database. Comorbidities - intracerebral hemorrhage (431), cerebrovascular anomaly (747.81), congestive heart failure (428.0), anemia (285.9) were also identified using the ICD-9 coding system. Descriptive and inferential statistical analysis were performed using SAS 2015. Results: A total of 842 HHT patients were identified with relatively older patients having increased prevalence of anemia (29% vs 15%), congestive heart failure (16% vs 8%), intra-cerebral hemorrhage (0.5% vs 0.3%), hypertension (47% vs 42%) compared to general population, respectively. We report HHT to be linked with having higher odds (p &lt; 0.05) of congestive heart failure (1.6 times), chronic pulmonary lung disease (1.7 times), liver disease (3 times), anemia (1.6 times), cerebrovascular anomaly including cerebral AVMs (26 times), and other neurological disorders than patients without HHT, after adjusting for confounders. Conclusion: This is the first database study confirming higher prevalence of CHF in HHT. We infer that chronic anemia and AVM/AVF can cumulatively cause high output congestive heart failure causing increased morbidity and mortality in HHT population especially in advanced ages.

Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).

The cerebral cavernous malformation 3 gene is necessary for senescence induction.

Mutations in cerebral cavernous malformation 3 gene are known to result in development of vascular malformations and have recently been proposed to also give rise to meningiomas. We report in this study that lack of CCM3 unexpectedly impairs the senescence response of cells, and this is related to the inability of CCM3-deficient cells to induce the C/EBPβ transcription factor and implement the senescence-associated secretory phenotype. Induction of C/EBPβ and cytokines is also impaired in the absence of CCM3 in response to cytokines in nonsenescent cells, pointing to it being a primary defect and not secondary to impaired senescence. CCM3-deficient cells also have a defect in autophagy at late passages of culture, and this defect is also not dependent on impaired senescence, as it is evident in immortal cells after nutrient starvation. Further, these two defects may be related, as enforcing autophagy in CCM3-deficient late passage cells increases C/EBPβ cytokine expression. These results broaden our knowledge on the mechanisms by which CCM3 deficiency results in disease and open new avenues of research into both CCM3 and senescence biology.

A life-threatening complication of Ehlers–Danlos syndrome

Ehlers-Danlos syndrome predisposes to the development of vascular malformations, which may present as life-threatening haemorrhage. This article presents a patient with Ehlers-Danlos syndrome in whom spontaneous rupture of an unusual arteriovenous fistula occurred. This rare diagnosis can be reached through close attention to the history and examination.

Molecular Pathogenesis of Vascular Anomalies: Classification into Three Categories Based upon Clinical and Biochemical Characteristics

Vascular tumors and malformations can be challenging to diagnose. Although they can resemble one another, their classification into tumors, such as hemangiomas of infancy, and malformations, such as venous or arteriovenous malformations, is based not only on their divergent biological behavior, but also on their pathogenesis. This review examines the molecular pathobiology of the processes involved in the development of these vascular birthmarks as they are currently understood. The terms hemangioma, hemangiosarcoma, and vascular proliferation are often used interchangeably, even though these entities are clinically and biochemically distinct. A more precise classification is necessary to facilitate communication between basic scientists and clinicians. Vasculogenesis, the in situ differentiation of blood vessels, occurs very early in the developing embryo. In vivo and in vitro studies, as well as knockout models, seem to indicate that this mechanism is unlikely to be involved in the development of either vascular malformations or hemangiomas of infancy. Recent advances in embryonic angiogenesis, especially explorations of mechanisms of vascular remodeling, have brought new understanding of the pathogenesis of vascular malformations. Vascular remodeling, an integral part of angiogenesis that centers upon the interactions between pericytes and endothelial cells, has been shown to be defective in certain experimental models and in some familial cases of vascular malformation. The occurrences of arteriovenous malformations in territories susceptible to increased remodeling also point towards epigenetic events in the development of vascular malformations.