Abnormalities in the Von Willebrand-Angiopoietin Axis Contribute to Dysregulated Angiogenesis and Angiodysplasia in Children With a Glenn Circulation

Bartoli, Carlo; Hennessy-Strahs, Samson; Dowling, Robert D.; Gaynor, J. William; Glatz, Andrew C.

doi:10.1016/j.jacbts.2020.12.014

Cited by 10 publications

(7 citation statements)

References 54 publications

(43 reference statements)

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“…Indeed, abnormalities in vWF metabolism are associated with angiodysplasia and arteriovascular malformations in multiple diseases [39][40][41][42][43][44][45][46]. In infants with single ventricle anatomy and a superior-cavopulmonary (Glenn) circulation, abnormalities in vWF and angiopoietin 2 play a role in the development of pulmonary angiodysplasia and arteriovascular malformations also without increased VEGF [47]. High shear stress from continuous-flow left ventricular assist devices increases enzymatic degradation of large vWF multimers into vWF degradation fragments [37], which may alter circulating levels of angiopoietin 2 [48] and cause mucosal arteriovascular malformations [37,38].…”

Section: Discussionmentioning

confidence: 99%

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

et al. 2021

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Hepatopulmonary syndrome affects 10–30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation.The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography, and absence of lung disease.We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median [interquartile range] 15 [12, 19] versus 14 [10, 17], p=0.006). Hepatopulmonary syndrome patients had significantly lower six minute walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin-2, Tie2, tenascin-C, c-kit, VCAM-1, and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80 [1.03–3.16], p=0.04) which persisted despite adjustment for covariates (hazard ratio 1.79 [1.02–3.15], p=0.04). This association did not vary based on levels of oxygenation reflecting the severity of hepatopulmonary syndrome.Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

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Section: Discussionmentioning

confidence: 99%

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

et al. 2021

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“…Altogether, these data further support that sVEGFR1 may have a role in PAVM pathophysiology given that sVEGFR1 sequesters VEGF-A to decrease VEGF-A bioavailability and signaling. Two recent studies have also reported that Angiopoietin-2 is elevated in patients with palliated univentricular CHD compared to patients with biventricular CHD (6,29). Angiopoietin-2 is associated with vascular remodeling, but these studies found no difference in ANG-2 levels in HV blood compared to paired SVC blood.…”

Section: Discussionmentioning

confidence: 92%

“…On the other hand, ANG1 is associated with promoting vascular homeostasis. Bartoli et al ( 29 ) reported decreased levels of ANG1 in SVC plasma compared to HV plasma and compared to healthy controls. Our quantitative array showed contradictory results with increased ANG1 levels in SVC serum compared to HV serum (HV: 1774.20 [665.51, 2251.92] pg/ml, SVC: 5755.66 [3237.47, 7933.60] pg/ml; Figure 1C , Supplementary Table 1 ), although these data are from a small sample ( n = 7).…”

Section: Discussionmentioning

confidence: 99%

sVEGFR1 Is Enriched in Hepatic Vein Blood—Evidence for a Provisional Hepatic Factor Candidate?

et al. 2021

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Background: Pulmonary arteriovenous malformations (PAVMs) are common sequelae of palliated univentricular congenital heart disease, yet their pathogenesis remain poorly defined. In this preliminary study, we used paired patient blood samples to identify potential hepatic factor candidates enriched in hepatic vein blood.Methods: Paired venous blood samples were collected from the hepatic vein (HV) and superior vena cava (SVC) from children 0 to 10 years with univentricular and biventricular congenital heart disease (n = 40). We used three independent protein analyses to identify proteomic differences between HV and SVC blood. Subsequently, we investigated the relevance of our quantified protein differences with human lung microvascular endothelial assays.Results: Two independent protein arrays (semi-quantitative immunoblot and quantitative array) identified that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is significantly elevated in HV serum compared to SVC serum. Using ELISA, we confirmed the previous findings that sVEGFR1 is enriched in HV serum (n = 24, p < 0.0001). Finally, we studied the quantified HV and SVC serum levels of sVEGFR1 in vitro. HV levels of sVEGFR1 decreased tip cell selection (p = 0.0482) and tube formation (fewer tubes [p = 0.0246], shorter tube length [p = 0.0300]) in vitro compared to SVC levels of sVEGFR1.Conclusions: Based on a small heterogenous cohort, sVEGFR1 is elevated in HV serum compared to paired SVC samples, and the mean sVEGFR1 concentrations in these two systemic veins cause pulmonary endothelial phenotypic differences in vitro. Further research is needed to determine whether sVEGFR1 has a direct role in pulmonary microvascular remodeling and PAVMs in patients with palliated univentricular congenital heart disease.

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“…Angiopoietin signaling is associated with vascular dysplasias, and angiopoietin-2 (ANGPT2) is a protein that promotes vascular remodeling in multiple vascular beds. These studies reported increased ANGPT2 levels in patients with Fontan ( 11 ) and Glenn circulation ( 12 ) compared to control patients with biventricular circulation. Both studies reported no difference in ANGPT2 levels between the SVC/pulmonary artery and inferior vena cava/hepatic vein.…”

Section: More Recent Hepatic Factor Studies Using Paired Patient Bloo...mentioning

confidence: 96%

“…Two additional studies independently identified that angiopoietin signaling may be a critical component of vascular remodeling in univentricular circulation ( 11 , 12 ). Angiopoietin signaling is associated with vascular dysplasias, and angiopoietin-2 (ANGPT2) is a protein that promotes vascular remodeling in multiple vascular beds.…”

Section: More Recent Hepatic Factor Studies Using Paired Patient Bloo...mentioning

confidence: 99%

Hepatic factor may not originate from hepatocytes

Merbach

Ramchandran

Spearman

2022

Front. Cardiovasc. Med.

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Pulmonary arteriovenous malformations (PAVMs) develop universally in patients with univentricular congenital heart disease. They are believed to form due to lack of an unidentified factor from hepatocytes that perfuses the lungs to maintain vascular homeostasis and prevent PAVM formation. This unidentified factor is termed hepatic factor; however, the identity, mechanism, and origin of hepatic factor are unknown. Several hepatic factor candidates have been previously proposed, but few data are available to support previous hypotheses. Recent data showed that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is enriched in hepatic vein blood and may be a potential hepatic factor candidate. We used imaging and molecular approaches with wild-type mice to determine whether sVEGFR1 originates from hepatocytes in the liver. To our surprise, we identified that sVEGFR1 is negligibly expressed by hepatocytes but is robustly expressed by the non-parenchymal cell population of the liver. This suggests that hepatic factor may not originate from hepatocytes and alternative hypotheses should be considered. We believe it is necessary to consider hepatic factor candidates more broadly to finally identify hepatic factor and develop targeted therapies for CHD-associated PAVMs.

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Abnormalities in the Von Willebrand-Angiopoietin Axis Contribute to Dysregulated Angiogenesis and Angiodysplasia in Children With a Glenn Circulation

Abstract: Visual Abstract

Cited by 10 publications

References 54 publications

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis

sVEGFR1 Is Enriched in Hepatic Vein Blood—Evidence for a Provisional Hepatic Factor Candidate?

Hepatic factor may not originate from hepatocytes

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