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

Abstract

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.

Pulmonary Vascular Sequelae of Palliated Single Ventricle Circulation: Arteriovenous Malformations and Aortopulmonary Collaterals

“…It remains unknown if these findings reflect a different stage of PAVM pathogenesis or are unrelated to in vivo physiology. Subsequently, we also observed multiple differences in circulating protein levels between the SVC and HV, including proteins involved in vascular angiogenic pathways and inflammatory pathways [43]. In this study, our group proposed soluble vascular endothelial growth factor receptor 1 (sVEGFR1) as a potential hepatic factor candidate.…”

“…In addition to the study by Capasso et al, several recent studies collected paired blood samples from the SVC (lacking hepatic factor) and IVC/HV (rich in hepatic factor) in attempts to characterize the differences between SVC and HV blood [42][43][44]. Using serum from a heterogenous group of patients composed of biventricular and single ventricle CHD, we incubated primary human pulmonary microvascular ECs with patient serum samples.…”

Hepatic factor may not originate from hepatocytes

“…Several groups recently started analyzing paired blood samples from the hepatic vein and SVC under the premise that hepatic factor is enriched in hepatic vein blood ( 9 – 13 ). In one of the first publications using this approach, Capasso et al investigated whether BMP9 and BMP10 were potential hepatic factor candidates ( 10 ).…”

“…Last, we recently identified that soluble vascular endothelial growth factor receptor 1 (sVEGFR1, also known as sFLT1) was significantly enriched in hepatic vein serum compared to SVC serum from a heterogenous cohort of children with CHD ( 13 ). Because increased VEGF signaling is associated with AVMs and supplemental sVEGFR1 can inhibit brain AVMs ( 14 – 17 ), we speculated that sVEGFR1 may be a potential hepatic factor candidate.…”

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

“…Although the lack of hepatic venous effluent directly perfusing the pulmonary arteries and the loss of pulsatile pulmonary blood flow have been identified as major etiological factors contributing to the development of PAVMs, their pathogenetic mechanism still remains unclear ( 1 ). Spearman et al ( 2 ) suggested that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) could be a potential hepatic factor candidate involved in the pathogenesis of PAVMs after surgical palliation for patients with univentricular heart.…”