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

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.

Vascular calcification in different arterial beds in ex vivo ring culture and in vivo rat model

“…In addition to calcification, the VDN model was associated with more marked fibrosis in the carotid artery than in aorta. The concomitant observation of fibrosis and medial calcification was previously reported in ex vivo vascular ring culture 19 , diabetic mice 30 , hypertensive mice with elastic fibres disorder 31 as well as in a rat model of calcification in chronic kidney disease 32 . On the other hand, a role for apoptosis in vascular calcification was evidenced in vascular smooth muscle cell culture 33 and in the VDN rat model 34 .…”

Vascular Calcification in Different Arterial Beds in Ex Vivo Ring Culture and in Vivo Rat Model

“…In addition to calci cation, the VDN model was associated with more marked brosis in the carotid artery than in aorta. The concomitant observation of brosis and medial calci cation was previously reported in ex vivo vascular ring culture 19 , diabetic mice 26 , hypertensive mice with elastic bres disorder 27 as well as in a rat model of calci cation in chronic kidney disease 28 . On the other hand, a role for apoptosis in vascular calci cation was evidenced in vascular smooth muscle cell culture 29 and in the VDN rat model 30 .…”

In silico analysis and verification of critical genes related to vascular calcification in multiple diseases

“…If the tubular flow decreases or the sodium chloride concentration drops, the juxtaglomerular cells of the afferent arterioles will release renin in response 25,26 . Moreover, aorta thickness could be significantly increased in DOCA‐salt hypertension mice as compared to normal mice 27 . On the contrary, steroid‐induced ocular hypertension often affects ocular diseases such as glaucoma by the accumulation of extracellular matrix in ocular vasculature, 28 not in the aorta.…”