Absence of pro-protein convertase subtilisin/kexin 6 increases flow-mediated outward remodeling in the mouse carotid artery.

Introduction - Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines but their function in vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques, localization to smooth muscle cells in the fibrous cap and positive correlation to inflammation, extracellular matrix remodeling and cytokines. Here, our aim was to evaluate the effects of PCSK6 on flow-mediated vascular remodeling in mice using high-frequency ultrasound and myography. Methods - PCSK6 -/- and C57Bl/6J mice were compared in this study divided in baseline control and increased flow groups. Increased flow was created in the right common carotid artery (CCA) by ligation of the left CCA. All animals were subjected to high-frequency ultrasound examination prior to surgery, at 3 and 5 weeks after surgery. Upon euthanization 6 weeks post-surgery the right CCA was harvested for myography evaluation, subsequently fixed at optimal stretch and prepared for histological evaluation. Results - The vascular circumference at optimal stretch in myography was strongly correlated (Pearson r=0.74, p<0.001) and in agreement with the diastolic circumference measured by high-frequency ultrasound in examined animals. A significant increase in diastolic circumference was seen at 3 and 5 weeks after surgery in PCSK6 -/- mice with increased flow compared to PCSK6 -/- control group (1.6±0.15 mm vs 1.4±0.08 mm, p<0.05 and 1.7±0.09 mm vs 1.4±0.12 mm, p<0.01). Myography revealed a significant increase in circumference at optimal stretch (1.7±0.21 mm vs 1.4±0.08 mm, p<0.05) in PCSK6 -/- mice subjected to increased flow compared to PCSK6 -/- control group. A significant flow-mediated increase in medial contractility was identified (0.68±0.14 mN/mm vs 0.45±0.11 mN/mm, p<0.05) in C57Bl/6J mice compared to C57Bl/6J control where as an absence of flow-mediated increase in medial contractility was seen in PCSK6 -/- mice. Conclusion - Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.