Abstract 18474: Impact of the Endothelial Nucleotidase on Vascular Function

Abstract

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Endothelial dysfunction—marked by poor endothelial-derived vasodilation—is a major prelude to atherosclerotic cardiovascular disease. Endothelial cells (EC) play a vital role in modulating thrombosis, atherosclerosis, and blood flow. One tool the endothelium uses to communicate with surrounding tissues is purinergic signaling. EC express both purinergic receptors to respond to stimuli and ectonucleotidases to facilitate this communication. CD39 is believed to be vital in maintaining homeostasis within the vasculature as it is an ectonucleotidase responsible for converting extracellular ATP and ADP into AMP. However, little is known about the role of endothelial expressed CD39 on vascular function. Hypothesis: We hypothesized that the absence of endothelial CD39 causes an elevation in extracellular adenine-nucleotides, thus causing an elevated endothelial-derived vasodilatory response. Methods: We generated a novel cre-lox endothelial cell-specific CD39 knockout mouse model ( Tie2cre+ CD39flox/flox ) to explore the enzyme’s role in vascular physiology. After validation via flow cytometry and enzyme activity assays, we assessed mouse blood pressure along with EC-derived vasodilatory capacity. Coronary vasodilatory capacity or coronary flow reserve (CFR) was measured via an isoflurane-induced-vasodilation coronary flow model and imaged using transthoracic ultrasound. Results: We noted that the EC specific CD39 knockout mice (EC-cKO) exhibited significantly lower systolic, diastolic, and mean arterial blood pressures at baseline, showing the EC-cKO mice having reduced pressures of over 10mmHg compared to wild-type (EC-WT) (p<0.05). This suggested fundamental differences in vascular function, prompting assessment of CFR. The EC-cKO mice showed a 75.9% increase in CFR (p<0.05) compared to wild-type (EC-WT). Conclusions: The loss of CD39 on EC leads to an overall protective phenotype—EC-cKO mice show drastically lower blood pressures, likely due to improved vasodilatory capacity under healthy conditions. This study shows CD39 inhibition’s potential as a therapeutic target in terms of improving vascular function.