PDGF regulates guanylate cyclase expression and cGMP signaling in vascular smooth muscle

Staffan Hildebrand,Mohamed Ibrahim,Alexander Pfeifer,Lars Maegdefessel,Andreas Schlitzer,Wilhelm Röll

doi:10.1038/s42003-022-03140-2

Abstract

The nitric oxide-cGMP (NO-cGMP) pathway is of outstanding importance for vascular homeostasis and has multiple beneficial effects in vascular disease. Neointimal hyperplasia after vascular injury is caused by increased proliferation and migration of vascular smooth muscle cells (VSMCs). However, the role of NO-cGMP signaling in human VSMCs in this process is still not fully understood. Here, we investigate the interaction between platelet derived growth factor (PDGF)-signaling, one of the major contributors to neointimal hyperplasia, and the cGMP pathway in vascular smooth muscle, focusing on NO-sensitive soluble guanylyl cyclase (sGC). We show that PDGF reduces sGC expression by activating PI3K and Rac1, which in turn alters Notch ligand signaling. These data are corroborated by gene expression analysis in human atheromas, as well as immunohistological analysis of diseased and injured arteries. Collectively, our data identify the crosstalk between PDGF and NO/sGC signaling pathway in human VSMCs as a potential target to tackle neointimal hyperplasia.

Highlights

The nitric oxide-cGMP (NO-cGMP) pathway is of outstanding importance for vascular homeostasis and has multiple beneficial effects in vascular disease
To study the effect of platelet derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs), we stimulated human aortic VSMCs with recombinant PDGF-BB
To directly test our hypothesis, we focused on peripheral artery disease (PAD), which is characterized by a pronounced neointimal hyperplasia and a dramatic increase in PDGF-B expression in the vascular wall[63]

Summary

Introduction

The nitric oxide-cGMP (NO-cGMP) pathway is of outstanding importance for vascular homeostasis and has multiple beneficial effects in vascular disease. The overall beneficial effects of NO has prompted much research targeting components of the NO-cGMP pathway to reduce neointima formation, the results are so far not conclusive: Several animal studies have shown great promise in reducing vascular occlusion by local gene transfer of NO synthases[23], sGC24, and protein kinase G (PKG, the primary receptor for cGMP)[25]. Two human trials have investigated the effect of NO donors on restenosis after coronary balloon angioplasty[30,31], and only one showed a modest decrease in restenosis rate, but no effect on luminal narrowing or clinical outcome[31] This discrepancy underlines the importance of further studies into the regulation of the NO-cGMP pathway and its potential interaction with the PDGF pathway in VSMC. We show that activation of the PDGFβ receptor in VSMCs reduces the expression of sGC in neighboring human

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