Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice

Abstract

Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice. Pcsk6−/− and wild type mice were randomized into control and increased blood flow groups and induced in the right common carotid artery (CCA) by ligation of the left CCA. The animals underwent repeated ultrasound biomicroscopy (UBM) examinations followed by euthanization with subsequent evaluation using wire myography, transmission electron microscopy or histology. The Pcsk6−/− mice displayed a flow-mediated increase in lumen circumference over time, assessed with UBM. Wire myography revealed differences in the flow-mediated remodeling response detected as an increase in lumen circumference at optimal stretch with concomitant reduction in active tension. Furthermore, a flow-mediated reduction in expression of SMC contractile markers SMA, MYH11 and LMOD1 was seen in the Pcsk6−/− media. Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.

Association of PCSK6 polymorphisms with susceptibility risk of large artery atherosclerotic stroke

“…In 2020, Rykaczewska et al [18]has identi ed that PCSK6 is associated with carotid intima-medial thickness, is an index for atherosclerosis, and immunohistochemistry con rmed that PCSK6 localize in smooth muscle actin positive cells of the brous cap and the neovascular, PCSK6 is increased after arterial injury in a mice carotid artery balloon injury model, and the levels positively correlate with the level of some in ammatory factors such as PDGFB, MMP2/MMP14. Similarly, another study [19]…”

“…The development of atherosclerosis usually correlates with abnormal proliferation, migration and apoptosis of smooth muscle cells [25]. A recent study showed that PCSK6 gene silencing leads to downregulation of VSMC contractile markers and decreased MMP2 expression, instead, PCSK6 gene overexpression increases VSMC proliferation and migration induced by PDGFB [19]. A previous study [18] suggested that PCSK6 snps was associated with artery intima-media thickness, intimal thickening is considered to be a manifestation of atherosclerosis.…”

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

“…24 PCSK6 is a critical mediator of TGF- processing and is crucial for reproduction, embryological development and blood pressure regulation. 25-29 A PCSK6 gene variant has been implicated in the development of hypertension 29 and dysregulated PCSK6 gene expression has been linked to vascular disease, [30][31][32] and cardiac remodeling following myocardial ischemia. 33 These cardiovascular remodeling effects make PCSK6 of particular relevance to IPF, as PCSK6 overexpression can lead to increased collagen I and III deposition, TGF- activation and extracellular matrix formation, 33,34 which are cardinal features of IPF pathogenesis.…”

Proprotein Convertase Subtilisin/Kexin 6 in Cardiovascular Biology and Disease

“…In cultured human monocytes and endothelial cells, PCSK6 expression and activity are increased by pro-atherogenic lipid oxidation products [ 129 ]. In Pcsk6 KO mice, compromised vascular remodeling, as indicated by enlarged systolic and diastolic circumferences and reduced contractile SMC markers, is observed in carotid arteries exposed to increased blood flow [ 130 ]. Increased PCSK6 expression is also detected in smooth muscle α-actin (SMA) (an SMC marker) -positive cells in unstable carotid plaques, where inflammation and extracellular matrix degradation are active [ 131 ].…”