Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia

A Iriarte,L Ochoa-Callejero,J García-Sanmartín,P Cerdà,P Garrido,J Narro-Íñiguez,Jm Mora-Luján,A Jucglà,Ma Sánchez-Corral,F Cruellas,E Gamundi,J Ribas,J Castellote,F Viñals,A Martínez,A Riera-Mestre

doi:10.1016/j.ejim.2021.03.039

Abstract

BackgroundAdrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity. The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. MethodsSerum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. ResultsForty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1–80.6] pg/mL in the HHT group and 47.7 [43.2–53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. ConclusionsWe detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.

Highlights

Hereditary hemorrhagic telangiectasia (HHT) or Rendu –Osler–Weber syndrome (ORPHA774) is a rare autosomal dominant vascular disease characterized by telangiectases and larger vascular malformations (VMs) of the pulmonary, cerebral, or hepatic vasculature [1]
Pulmonary arteriovenous malformations (AVMs) and brain VMs are more common in patients with HHT1, while hepatic VMs are more common in HHT2 [9]
The elevated levels of AM found in our HHT patients may result from this faulty Bone morphogenetic protein 9 (BMP9) signaling, caused by mutations in endoglin or activin receptor-like kinase 1 (ALK1) proteins, causing the known dysregulation of the signaling hub formed by BMP9–Endoglin–ALK1–Smad [8,34,35]

Summary

Introduction

Hereditary hemorrhagic telangiectasia (HHT) or Rendu –Osler–Weber syndrome (ORPHA774) is a rare autosomal dominant vascular disease characterized by telangiectases and larger vascular malformations (VMs) of the pulmonary, cerebral, or hepatic vasculature [1]. Endoglin (encoded by ENG) is an auxiliary co-receptor at the endo thelial cell surface that promotes BMP9 (Bone morphogenetic protein 9) signaling through the activin receptor-like kinase 1 (ALK1; encoded by ACVRL1). Both proteins contribute to the signaling hub formed by BMP9–Endoglin–ALK1–Smad with high impact in endothelial cell (EC) proliferation, migration, and survival during angiogenesis. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. Methods: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies

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