Evidence of Cardiovascular Calcification and Fibrosis in Pseudoxanthoma Elasticum Mouse Models Subjected to DOCA-Salt Hypertension

Loukman Omarjee,Julie Favre,Ludovic Martin,Anne Janin,Charlotte Roy,Daniel Henrion,Gilles Kauffenstein,Georges Leftheriotis,Christophe Leboeuf,Guillaume Mahe

doi:10.1038/s41598-019-52808-z

Abstract

Pseudoxanthoma Elasticum (PXE) is a rare disorder characterized by fragmentation and progressive calcification of elastic fibres in connective tissues. Although arterial hypertension (AHT) has been reported in PXE patients, its impact on pathological manifestations has as yet been unexplored. We investigated the consequences of experimental AHT on Abcc6−/− PXE mouse models. Experimental AHT was induced by deoxycorticosterone acetate (DOCA-salt) in uni-nephrectomised mice. Blood pressure (BP) and vascular reactivity were monitored using tail-cuff plethysmography and myography respectively. Calcium content and fibrosis were assessed using colorimetry, Von Kossa and Sirius red staining respectively. The gene expression implicated in vascular biology was measured using quantitative polymerase chain reaction. DOCA-salt induced a matching rise in BP in Abcc6−/− and WT mice. Aortic ring contraction and relaxation in vitro were comparable. Calcium accumulated in the hearts of hypertensive Abcc6−/− mice along with significant fibrosis in the myocardium and aorta by contrast with the WT mice. In hypertensive Abcc6−/− mouse aortas, these results were corroborated by gene expression patterns favouring calcification, fibrosis and extracellular matrix remodelling. Abcc6 loss-of-function is associated with greater cardiovascular calcification and fibrosis in mice subjected to DOCA-Salt hypertension. These results suggest likely cardiovascular deterioration in PXE patients with AHT, necessitating diligent BP monitoring.

Highlights

Blood Pressure (MBP), Pulse Pressure (PP) in mmHg and heart rate (HR) as beats per minute of untreated and deoxycorticosterone acetate (DOCA)-salt-treated mice
Abcc6−/− and WT mice were submitted to deoxycorticosterone acetate (DOCA)-salt-induced arterial hypertension (AHT), representing an experimental model characterized by an initial rise in AHT over the first few days followed by sustained elevated Blood pressure (BP) for weeks[13]
DOCA-salt treatment caused a progressive rise in systolic blood pressure (SBP) over a period of 19 days in Abcc6−/− and WT mice (Fig. 1)

Summary

Introduction

Blood Pressure (MBP), Pulse Pressure (PP) in mmHg and HR as beats per minute (bpm) of untreated and DOCA-salt-treated mice. There is a higher risk of vascular events in PXE patients than in the general population, presumably resulting from arterial medial calcification along with arterial stiffening and thickening[8]. Around 20–25% of PXE patients present CV complications related to high morbidity and mortality such as higher prevalence of accelerated atherosclerosis involving greater risk of complete vascular occlusion[10,11]. Abcc6−/− and WT mice were submitted to deoxycorticosterone acetate (DOCA)-salt-induced AHT, representing an experimental model characterized by an initial rise in AHT over the first few days followed by sustained elevated BP for weeks[13]. Our aim was to investigate the consequences of DOCA-salt-induced AHT on CV reactivity and remodelling in Abcc6−/− mice by comparison with WT mice

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Conclusion