Formation Of Arteriovenous Malformations Research Articles

Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder resulting in vascular dysplasia and formation of arteriovenous malformations. Recurrent epistaxis is a hallmark of the disease. An array of medical therapies are used in this patient population, but robust evidence-based recommendations regarding the medical treatment of epistaxis are lacking. This systematic review was performed to look at the current literature and make meaningful evidence-based recommendations. A search of the Ovid MEDLINE, Embase, and Cochrane databases was conducted by a research librarian. Abstracts in the English language and published in a peer-review journal were reviewed for relevance and inclusion. PRISMA guidelines were followed. Eighteen studies met the inclusion criteria. In a few small studies, thalidomide was shown to consistently improve severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion. Tranexamic acid appeared to only impact the epistaxis severity score and not other clinical outcomes. Selective estrogen modulators (SERMs), propranolol, rose geranium oil, and N-acetylcysteine, have demonstrated promising efficacy in small trials. Appropriate medical therapies for epistaxis outcomes in HHT remain undefined, and there is no "gold standard." Many of the studies are small and the data reported are heterogeneous, and therefore the ability to make strong evidence-based recommendations is limited. However, many different medications appear to be promising options.

Abstract 21207: Use of Digoxin, an Inhibitor of Hypoxia Inducible Factor 1A Synthesis, is Associated With Decreased Incidence of Gastrointestinal and Arteriovenous Malformations Related Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device

Introduction: Gastrointestinal bleeding (GIB) occurs in 20-40% of patients with continuous flow left ventricular assist device (CF-LVAD) during the first years of follow up and is most commonly due to arteriovenous malformations (AVM). Although the precise pathophysiology of AVM formation during CF-LVAD support has not been established, it is postulated that hypoperfusion in the splanchnic vascular territory and resultant hypoxia may activate the angiogenesis signaling cascade via the HIF1α/angiopoietin-2 pathway. Interestingly, digoxin is a potent inhibitor of HIF1α synthesis. Hypothesis: We hypothesize that digoxin therapy can be associated with a decrease incidence of GI and AVM bleeding in CF-LVADs patients. Methods: Charts of all adult patients implanted with CF-LVAD between February 2006 and February 2017 were reviewed with emphasis on occurrence and etiology of GIB. Kaplan Meier (KM) and logistic regression analysis were used to assess the frequency of overall GI and AVM bleeding and their association with digoxin therapy. Results: Sixty-two of 204 patients (30%) experienced a GIB and 20 of 62 (32%) bleeds were due to AVM. Both overall frequency of GIB (18% vs 37% of patients, p < 0.05) and AVM bleeding (3% vs 14% of patients, p < 0.05) were lower in the 73 patients receiving digoxin compared to the 131 patients not receiving digoxin during an average observation time of 516 and 446 days, respectively. Survival free of GIB was significantly higher in digoxin treated patients in KM analysis (Fig1). Multivariate logistic regression analysis revealed that digoxin therapy was independently associated with a reduced risk for overall GIB (odds ratio 0.35, 95% confidence interval 0.17-0.75) as well as AVM bleeding (odds ratio 0.19, 95% confidence interval 0.35-0.52). Conclusions: Use of digoxin was associated with a significant reduction in overall GIB as well as AVM bleeding. Prospective studies are needed to validate this finding and its mechanistic underpinnings.

De novo AVM formation following venous sinus thrombosis and prior AVM resection in adults: report of 2 cases

Brain arteriovenous malformations (AVMs) are traditionally considered congenital lesions, arising from aberrant vascular development during the intrauterine period. Rarely, however, AVMs develop in the postnatal period. Individual case reports of de novo AVM formation in both pediatric and adult patients have challenged the traditional dogma of a congenital origin. Instead, for these cases, a dynamic picture is emerging of AVM growth and development, initially triggered by ischemic and/or traumatic events, coupled with genetic predispositions. A number of pathophysiological descriptions involving aberrant angiogenic responses following trauma, hemorrhage, or inflammation have been proposed, although the exact etiology of these lesions remains to be elucidated. Here, the authors present 2 cases of de novo AVM formation in adult patients. The first case involves the development of an AVM following a venous sinus thrombosis and to the authors' knowledge is the first of its kind to be reported in the literature. They also present a case in which an elderly patient with a previously ruptured AVM developed a second AVM in the contralateral hemisphere 11 years later. In addition to presenting these cases, the authors propose a possible mechanism for de novo AVM development in adult patients following ischemic injury.

Abstract 125: Increased Endothelial Endoglin Gene Deletion and Co-deletion of EphrinB2 Enhance Brain Arteriovenous Malformation in Mice

Introduction: Endoglin (Eng) is an arteriovenous malformation (AVM) causative gene. In adult mice, global Eng deletion induced by a wild-type cre (cre) results in AVM formation in the brain angiogenic region. We hypothesize that using a codon-improved cre (icre) to increase Eng gene deletion in endothelial cells and co-deletion of the EphrinB2 gene, a determinant of arterial endothelial differentiation, will enhance brain AVM severity. Methods: Eng was globally deleted in adult Eng -floxed mice ( Eng 2f/2f ) using a rosa promoter driving estrogen inducible cre (Rosa-creER), or in endothelial cells using a platelet-derived growth factor b promoter driving estrogen inducible icre ( pdgfb- icreER). Pdgfb- icreER was also used to mediate endothelial deletion of EphrinB2 . An adeno-associated viral vector expressing vascular endothelial growth factor was injected into the brain to induce brain angiogenesis. Results: Compared with Rosa-CreER-mediated global Eng deletion, pdgfb- icreER-induced endothelial Eng deletion did not increase the number of abnormal vessels (P=0.39), but reduced vascular smooth muscle coverage (P=0.03) and increased hemorrhage (P=0.04) in the brain AVM lesion. Additional endothelial deletion of EphrinB2 gene increased the number of abnormal vessels in the brain (P=0.08). Conclusion: These data indicate that a positive correlation exists between the degree of gene mutation in the endothelial cells and brain AVM severity, and that dysregulation of endothelial arteriovenous specification enhances AVM formation and progression.

Abstract TMP113: Deletion of Alk1 Gene in Bone Marrow-Derived Endothelial Cells is Sufficient to Cause Brain Arteriovenous Malformation in Mice

Introduction: In humans, Alk1 deficiency causes arteriovenous malformations (AVMs) in multiple organs. Endothelial deletion of Alk1 in adult mice leads to AVM formation in multiple organs and the brain angiogenic region, and endoglin-deficient bone marrow (BM) transmits abnormal brain vascular phenotype to wild-type (WT) mice. We hypothesize that Alk1 deletion in BM-derived endothelial cells (BMDECs) is sufficient to induce AVM in the brain angiogenic region in adult mice. Methods: Adult pdgf b-iCreER; Alk1 2f/2f mice that have Alk1 exons 4-6 flanked by loxP sites and a transgene expressing tamoxifen (TM)-inducible cre recombinase in the endothelial cells were used as BM donor. BM isolated from these mice was transplanted to lethally irradiated 8-week-old WT mice. Brain angiogenesis was induced through an intra-brain injection of an adeno-associated viral vector expressing VEGF 4 weeks after the BM transplantation. Two weeks later, Alk1 deletion was induced through an intra-peritoneal injection of TM (2.5 mg/20g body weight). Vascular morphology was analyzed using latex casting 6 weeks later. Results: Peripheral blood cell counts fully recovered in the recipients 4 weeks after BM transplantation. Mice transplanted with pdgfb -iCreER; Alk1 2f/2f BM developed AVM in the brain angiogenic region. BM-derived endothelial cells were detected in brain AVM vessels. Unlike pdgfb -iCreER; Alk1 2f/2f mice that died 2 weeks after TM treatment due to bleeding from intestinal AVM, mice with pdgfb -iCreER; Alk1 2f/2f BM stayed alive within a 6-week period after TM treatment, suggesting that their intestinal AVM was less severe than in pdgfb -iCreER; Alk1 2f/2f mice. Conclusion: BMDECs play a significant role in brain AVM development. Transfusion of endothelial progenitor cells or stem cell-derived endothelial cells could be a potential therapy for brain AVM patients.

Abstract 120: Radiocarbon Birth Dating of Cerebral Arteriovenous Malformations

Introduction: The chronological development of brain arteriovenous malformations (AVM) is controversial. Atmospheric nuclear testing until 1963 produced a global bomb-pulse of 14 C and thus a chronometer of molecular synthesis in the entire biosphere from 1955 to the present. We isolated and dated a durable, representative structural protein from human cerebral arteries (CA) and brain AVMs. Method: Samples from cadaveric CAs or from brain AVMs from patients undergoing surgical resection were processed to ultra- purify elastin. The age of purified elastin extracted from cerebral arteries or from AVMs was measured using 14 C bomb-pulse technique. We modified a 14 C biological incorporation equation model using variable AVM formation dates and elastin formation and degradation rates. Results: A total of 62 CAs from individuals with ages ranging from 1 month to 100 years and 30 unruptured or ruptured AVMs were collected. All CAs and nearly all AVMs yielded ultra-purified elastin in sufficient amount for further 14 C birth dating. Mean age of elastin was 13.4± 11.2 years (n = 34), whereas elastin derived from AVMs was less than 5 years old (n = 15, p = 0.002). Based on 14 C content relative subject birthdate and date of tissue collection, best-fit modeling of CA and AVM elastin demonstrated turnover rates less than 2% and 25 - 50%, respectively. Amongst AVMs, those with associated aneurysms had younger elastin (p=0.007). Larger AVMs tended to have younger elastin (p=0.086) and AVM rupture was not associated with elastin age (p=0.358). Conclusions: Our data provides the first chronological evidence for the longevity of elastin in CAs, as evident based on the inclusion of bomb carbon in elastin from subjects who reached maturity prior to 1955. Importantly it also demonstrates elastin isolated from brain AVMs is contemporary and likely immature suggesting a non-congenital origin and/or rapid vascular turnover.

Guitarist Pick for Melena: A Unique Case of an Upper GI Bleed

Gastrointestinal bleeds are a commonly observed complication after left ventricular assist device placement and usually caused by formation of arteriovenous malformations or acquired von Willebrand disease in the setting of anticoagulation use. We present a unique case of an upper GI bleed in which the cause was likely due to the impaction of a guitar pick into the duodenal bulb in the setting of continuous flow-LVAD on anticoagulation with elevated INR and discuss the pathophysiology of GI bleeds post-LVAD placement and relevant concerns about finding foreign bodies in the GI tract and their complications.

PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.

Activin receptor-like kinase 1 (ALK1) is an endothelial serine–threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.

Association of Nasal Mucosal Vascular Alterations, Gastrointestinal Arteriovenous Malformations, and Bleeding in Patients With Continuous-Flow Left Ventricular Assist Devices

ObjectivesThis study sought to determine whether the nasal mucosa can serve as a surrogate for evaluating arteriovenous malformations (AVMs) related gastrointestinal (GI) bleeding in patients supported by continuous-flow left ventricular assist devices (CF LVADs). BackgroundBleeding from the mucosal surfaces of GI tract, particularly AVMs, is the most common complication of CF LVAD support. The pathophysiology of AVM formation during CF LVAD support is of critical interest yet poorly understood; in large part because of the length and accessibility of the GI tract. Nasal endoscopy is a minimally invasive, bedside test giving access to a mucosal surface possibly representative of the GI tract. MethodsEighty subjects (35 with CF LVAD, 30 with heart failure reduced ejection fraction [HFrEF], and 15 controls without heart failure) underwent nasal endoscopy for systematic evaluation of the intranasal mucosa for the presence of hypervascularity (HV). Patient records were reviewed for episodes and etiology of GI bleeding. ResultsNasal HV was present in 63%, 57%, and 20% of the LVAD, HFrEF, and control groups, respectively (p = 0.018). Although the prevalence was similar, the severity of nasal HV was significantly higher in the CF LVAD group compared with the HFrEF group. Of the baseline characteristics in the entire cohort, only a history of heart failure was associated with HV (odds ratio: 4.8; 95% confidence interval: 1.02 to 22.31; p = 0.040) in adjusted logistic regression modeling. HV was strongly associated with GI bleeding in the CF LVAD cohort: the incidence was 32% in subjects with HV compared with 0% in subjects with normal mucosa (p = 0.023). ConclusionsIn this pilot study, HV of the nasal mucosa was associated with GI bleeding in subjects with CF LVADs. Nasal endoscopy has significant potential to further investigation into mechanisms of bleeding and risk stratification during CF LVAD support.

Abstract 380: Notch4 Uncouples Endothelial Nitric Oxide Synthase Leading to Arteriovenous Malformations

Notch is distinctively expressed in arterial but not venous endothelial cells. Notch signaling regulates arteriovenous (AV) specification, and mutations in Notch signaling lead to AV malformation (AVM) in mice. AVMs are characterized by abnormal AV shunts that displace capillaries. Mechanisms underlying AVM pathogenesis remain poorly understood, hindering therapeutic development. We reported that endothelial expression of constitutively active Notch4 (Notch4*) in mice initiates AVMs de novo through enlargement of microvessels without an increase in endothelial cell number or proliferation. Here, we hypothesized that Notch4* disrupts endothelial nitric oxide synthase (eNOS) signaling and vascular tone, thereby permitting vessel enlargement and AV shunting. We show that arteries isolated from Notch4* mutant mice exhibited decreased arterial tone compared to controls, suggesting that Notch4* impaired vascular tone. Administering the NOS inhibitor N G -nitro-L-arginine abolished Notch4*-mediated vascular tone impairment. Deletion of the eNOS gene and administration of the NOS inhibitor N G -nitro-L-arginine in the Notch4* mutant mice attenuated Notch4*-induced AVM initiation, measured by decreased AV shunt diameter, delayed AV shunting, reduced hemorrhage, pathological lesions, and improved survival, suggesting that eNOS is essential for Notch4* action. In addition, uncoupled eNOS-derived superoxide production was elevated in the Notch4* mice. Our results show that inhibition of eNOS signaling attenuates Notch4*-mediated AVM formation. Furthermore, Notch4* impairs eNOS activity, leading to superoxide production, which results in arterial dysfunction and AV shunt formation.

Abstract 10979: ACE-inhibitor or ARB Therapy Reduces the Risk for GI Bleeding in LVAD Patients

Introduction: Gastrointestinal bleeding (GIB) due to arteriovenous malformations (AVMs) is a major source of morbidity for patients supported with left ventricular assist devices (LVADs). Recent studies implicate angiogenesis mediated by vascular endothelial growth factor (VEGF) in AVM formation. Transforming growth factor-β is biochemically upstream of VEGF and is up-regulated after LVAD implantation. Angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) inhibit TGF-β. Hypothesis: ACE-inhibitor/ARB therapy will be independently associated with a reduced risk of GIB overall and GIB due to AVMs in LVAD patients. Methods: We reviewed the records of all patients aged 18 years or older receiving a continuous flow LVAD (HeartMate II or Heartware) at Johns Hopkins Hospital from 1/2004 to 9/2013 (n=186). We excluded patients for whom follow-up records were not available (n=3), those supported with a LVAD for less than 100 contiguous days (n=51), and those missing covariates included in statistical models (n=8), leaving 124 patients included for analyses. Cox proportional hazards models adjusted for demographic, cardiovascular, and laboratory variables were used to assess the association of ACE-inhibitor/ARB therapy with GIB. Results: Mean age of patients was 52 years and 75% were male. Ninety-seven patients received ACE-inhibitor and/or ARB therapy during LVAD support. Thirty-six patients (29%) had at least one GIB after discharge from their LVAD implantation; 15 of these 36 episodes (42%) were due to confirmed AVMs. Among ACE/ARB patients, 24% had a post-discharge GIB (23/97) versus 48% (13/27) of non-ACE/ARB patients. Fully adjusted Cox proportional hazards model demonstrated that ACE-inhibitor/ARB therapy was independently associated with a reduced risk of GIB after hospital discharge (HR 0.37, 95% CI 0.17-0.81, p=0.012) with suggestion of reduced risk of GIB due to AVMs (HR 0.32, 95% CI 0.10-1.06, p=0.06). Conclusions: ACE-inhibitor and ARBs are independently associated with a reduced risk of GIB in LVAD patients and should be considered for all LVAD patients without contraindications. Possible biologic mechanisms of this observation remain unexplored and warrant further investigation.

Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia.

Rendu–Osler–Weber syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant vascular disorder. Three genes are causally related to HHT: the ENG gene encoding endoglin, a co-receptor of the TGFβ family (HHT1), the ACVRL1 gene encoding ALK1 (activin receptor-like kinase 1), a type I receptor of the TGFβ family (HHT2), and the SMAD4 gene, encoding a transcription factor critical for this signaling pathway. Bone morphogenetic proteins (BMPs) are growth factors of the TGFβ family. Among them, BMP9 and BMP10 have been shown to bind directly with high affinity to ALK1 and endoglin, and BMP9 mutations have recently been linked to a vascular anomaly syndrome that has phenotypic overlap with HHT. BMP9 and BMP10 are both circulating cytokines in blood, and the current working model is that BMP9 and BMP10 maintain a quiescent endothelial state that is dependent on the level of ALK1/endoglin activation in endothelial cells. In accordance with this model, to explain the etiology of HHT we hypothesize that a deficient BMP9/BMP10/ALK1/endoglin pathway may lead to re-activation of angiogenesis or a greater sensitivity to an angiogenic stimulus. Resulting endothelial hyperproliferation and hypermigration may lead to vasodilatation and generation of an arteriovenous malformation (AVM). HHT would thus result from a defect in the angiogenic balance. This review will focus on the emerging role played by BMP9 and BMP10 in the development of this disease and the therapeutic approaches that this opens.

Gastrointestinal bleeding after continuous-flow left ventricular device implantation: review of pathophysiology and management.

Gastrointestinal bleeding is one of the most common complications in patients with continuous-flow left ventricular assist devices. Though the exact pathophysiology is still unclear, continuous-flow physiology, acquired Von Willebrand disease, and formation of arteriovenous malformations in the gastrointestinal tract are implicated. An individualized plan of endoscopic therapy and anticoagulation management is required when caring for these patients.

Animal Models in Studying Cerebral Arteriovenous Malformation.

Brain arteriovenous malformation (AVM) is an important cause of hemorrhagic stroke. The etiology is largely unknown and the therapeutics are controversial. A review of AVM-associated animal models may be helpful in order to understand the up-to-date knowledge and promote further research about the disease. We searched PubMed till December 31, 2014, with the term “arteriovenous malformation,” limiting results to animals and English language. Publications that described creations of AVM animal models or investigated AVM-related mechanisms and treatments using these models were reviewed. More than 100 articles fulfilling our inclusion criteria were identified, and from them eight different types of the original models were summarized. The backgrounds and procedures of these models, their applications, and research findings were demonstrated. Animal models are useful in studying the pathogenesis of AVM formation, growth, and rupture, as well as in developing and testing new treatments. Creations of preferable models are expected.

Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels.

Arteriovenous (AV) malformation (AVM) is a devastating condition characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. AVMs can form anywhere in the body and can cause debilitating ischemia and life-threatening hemorrhagic stroke. The mechanisms that underlie AVM formation remain poorly understood. Here, we examined the cellular and hemodynamic changes at the earliest stages of brain AVM formation by time-lapse two-photon imaging through cranial windows of mice expressing constitutively active Notch4 (Notch4*). AVMs arose from enlargement of preexisting microvessels with capillary diameter and blood flow and no smooth muscle cell coverage. AV shunting began promptly after Notch4* expression in endothelial cells (ECs), accompanied by increased individual EC areas, rather than increased EC number or proliferation. Alterations in Notch signaling in ECs of all vessels, but not arteries alone, affected AVM formation, suggesting that Notch functions in the microvasculature and/or veins to induce AVM. Increased Notch signaling interfered with the normal biological control of hemodynamics, permitting a positive feedback loop of increasing blood flow and vessel diameter and driving focal AVM growth from AV connections with higher blood velocity at the expense of adjacent AV connections with lower velocity. Endothelial expression of constitutively active Notch1 also led to brain AVMs in mice. Our data shed light on cellular and hemodynamic mechanisms underlying AVM pathogenesis elicited by increased Notch signaling in the endothelium.

Matrix Metalloproteinases and VEGF: Potential Roles in Formation of High‐Flow Vascular Anomalies

Objectives: Arteriovenous malformations (AVMs) are congenital vascular malformations that result from a defect in vascular morphogenesis. These lesions are slow-growing, infiltrative, and destructive resulting in significant morbidity associated with cardiac overload and increased susceptibility to massive bleeding. Recent evidence suggests a role of matrix metalloproteinases (MMPs), a family of enzymes functioning in tissue remodeling via degradation of extracellular matrix proteins and cleaving of surface molecules, in the pathogenesis of AVM development and rupture. This study sought to explore the role of MMPs, particularly MMP-9, in AVM formation and progression. Methods: Serum samples from patients with AVM, hemangioma, and pyogenic granuloma were collected and isolated at various stages of development. Relative quantities of MMP-2, MMP-9, and VEGF in each group were calculated and analyzed using sandwich-capture enzyme-linked immunosorbent assay. Results: MMP-2 concentrations were found to be decreased in AVM serum samples when compared with serum samples from the pyogenic granuloma controls (27.9 ± 5.97 vs 32.84 ± 2.20, P = 6.3 × 10–9); MMP-9 concentrations were found to be increased in AVM serum samples when compared with hemangioma serum samples (1698.81 ± 410.86 vs 1105.02 ± 239.43, P < .02); and VEGF concentrations were found to be decreased in AVM serum samples when compared with hemangioma serum samples (52.27 ± 63.02 vs 174.0 ± 9.84, P < .05). Conclusions: The results of this study provide support for a role of MMP-9 in AVM progression and recurrence. Specifically, an increase in MMP-9 appears to be associated with AVM formation and may play an important role in its pathogenesis.

A hierarchical model for the development of cerebral arteriovenous malformations

ObjectiveCerebral arteriovenous malformations (AVMs) are vascular lesions whose pathogenesis, although not fully elucidated, is likely multifactorial. Recent research investigating vessel development suggests a potential hierarchical model in which capillary sprouts from higher-flow arteries give rise to lower-flow veins. It is possible that an embryologic structural vascular dysgenesis in this hierarchical development heavily contributes to the formation of AVMs. Subsequent genetic “second hits” may then allow development of a clinically significant cerebral AVM. We review this vascular developmental process and describe a novel proposal for the embryogenesis of AVMs and its implications in relation to recent research on polymorphisms and AVMs. MethodsA comprehensive literature search was performed using PubMed for recent research relative to cerebral AVMs, embryologic vascular development, and polymorphisms involved in AVM pathology. ResultsIt has recently been shown that both centrally, in the axial embryo, and peripherally, in the embryonic yolk sac, veins form via capillary sprouting from parent arteries. In developing intracranial vessels, a derangement in this embryonic process may lead to a primitive arteriovenous shunt. After this structural “first hit,” we suggest that single nucleotide polymorphisms (SNPs) are a major component in allowing AVM growth into symptomatic clinical lesions. ConclusionsThis is a novel theory for the embryologic formation of cerebral AVMs. Hierarchical vessel development, where higher-flow parent arteries give rise to lower-flow veins, provides a potential mechanism for the formation of primitive arteriovenous shunts that, with the influence of polymorphisms, allows AVMs to develop.

VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp(-/-)) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp(-/-) mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.

Left Ventricular Assist Devices and Gastrointestinal Bleeding: A Narrative Review of Case Reports and Case Series

The use of left ventricular assist devices (LVADs) has become a state-of-the-art therapy for advanced cardiac heart failure; however, multiple reports in the literature describe an increased risk for gastrointestinal (GI) bleeding in these patients. We characterized this association by reviewing recent studies on this topic. GI bleeding occurs frequently in patients with LVADs, especially with devices with nonpulsatile flow patterns. We performed a comprehensive literature review to identify articles that reported GI bleeding in patients with LVADs. Databases used included PubMed, EMBASE, Scopus, Web of Knowledge, and Ovid. Baseline and outcome data were then ed from these reports. We identified 10 case reports and 22 case series with 1543 patients. The mean age was 54.2 years. Most patients had nonpulsatile LVADs (1316, 85.3%). Three hundred and seventeen patients (20.5%) developed GI bleeding; this occurred more frequently in patients with nonpulsatile LVADs. Multiple procedures were performed without complications but often did not identify a definite bleeding site. Suspect lesions occurred throughout the GI tract but were more frequent in the upper GI tract. Many patients had arteriovenous malformations. All patients received medical therapy. None of the patients had their LVAD replaced. The use of anticoagulation did not appear to predispose these patients to more GI bleeding episodes. Patients with LVADs have frequent GI bleeds, especially from arteriovenous malformations, which can occur throughout the GI tract. Most diagnostic and therapeutic interventions can be used safely in these patients. The pathogenesis of the GI bleeding in these patients may involve the use of anticoagulant medications, the formation of arteriovenous malformations, loss of von Willebrand factor activity, and mucosal ischemia.