0356 : Disseminated arterial calcification and enhanced myogenic response are associated with Abcc6 deficiency in a mouse model of pseudoxanthoma elasticum

Abstract

Beside calcification, the impact of ABCC6 deficiency on the vasculature remains unclear. We investigated arterial structure and function in Abcc6-/- mice, a model of the human Pseudoxanthoma Elasticum (PXE). Arterial calcium accumulation determined by atomic absorption spectrometry was 1.5 – to 2-fold higher in Abcc6-/- than in wild-type mice. Calcium also accumulated locally leading to a specific punctuated pattern. Abcc6-/- mesenteric arteries mounted on a wire myograph displayed slight increase in arterial vasoconstrictor tone in response to phenylephrine and thromboxane A2. Interestingly, myogenic tone (Bayliss effect) determined using a pressure myograph was significantly elevated in Abcc6-/- compared to wild type arteries. Arterial blood pressure was not significantly modified in Abcc6-/- animals, despite higher variability. These changes were accompanied with deregulated gene expression (RTqPCR) in both liver and resistance arteries. Old Abcc6-/- mouse mesenteric arteries expressed markers of both osteogenic (Runx2, opn) and chondrogenic lineage (Sox9, col2a1). Surprisingly Enpp1 and Alpl genes encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 and alkaline phosphatase were deregulated within Abcc6-/- liver and this was corroborated with reduced alkaline phosphatase circulating levels in PXE patients. As a conclusion, scattered calcium depositions result from osteochondrogenic transdifferentiation of vascular cells. The lower elasticity and increased myogenic tone evidenced in aged Abcc6-/- mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis. Our findings argue in favor of a deregulated arterial function and may help to decipher consequences of ABCC6 deficiency since PXE is a significant risk factor for small vessel disease and particularly ischemic stroke.