Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling.

Tomokazu Sumida,Katsuki Okada,Jong-Kook Lee,Issei Komuro,Seitaro Nomura,Tomoaki Higo,Toshihiro Yamaguchi,Ichiro Shiojima,Hiroyuki Morita,Akito Nakagawa,Ichiro Manabe,Tetsuo Noda,Toshio Nagai,Akihito Hashimoto,Tohru Minamino,Masamichi Ito,Yoshio Kobayashi,Marina Botto,Atsuhiko T Naito,Stefan Offermanns,Hiroshi Akazawa,Tôru Oka ,Tomohiro Sakai

doi:10.1038/ncomms7241

Abstract

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates β-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of β-catenin signalling in hypertensive arterial remodelling. Activation of β-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of β-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced β-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of β-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension.

Highlights

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage
The number of 5-bromo-20deoxyuridine (BrdU)-positive, proliferating vascular smooth muscle cells (VSMCs) was significantly increased as early as 1 week after angiotensin II (AngII) infusion (Fig. 1d), when the gross structural remodelling of the arteries was not observed. These results suggest that VSMC proliferation is one of the earliest events that occur in response to AngII-induced blood-pressure elevation
Various growth factors and G-protein-coupled receptor agonists induce VSMC proliferation[7,19], and their mitogenic effects are often given by the activation of the mitogen-activated protein kinases, especially the extracellular signal regulated kinase (ERK) signalling pathway[5,20]

Summary

Introduction

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. We have recently reported that complement C1q activates b-catenin signalling independent of Wnts. A variety of humoral factors such as growth factors, proteases and cytokines, secreted by infiltrated immune cells, have been reported to be involved in VSMC proliferation[3,7], precise molecular and cellular mechanisms of how hypertensive arterial remodelling is developed remain elusive. Given that the major source of complement C1q is monocytederived cells[17] and that macrophages (Mfs) within the aortic wall play a vital role in pathogenesis of arterial remodelling, we hypothesized that aortic Mf-derived C1q activates b-catenin signalling and induces proliferation of VSMCs. In the present study, we elucidated that complement C1q, which is mainly secreted by alternatively activated aortic Mfs, is involved in hypertensive arterial remodelling via activation of b-catenin signalling

Methods

Results

Conclusion