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

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.

Gestational food restriction decreases placental interleukin-10 expression and markers of autophagy and endoplasmic reticulum stress in murine intrauterine growth restriction

“…We also demonstrated decreased levels of C1qa , a polypeptide chain of complement subcomponent C1q. Complement C1q-induced activation of β-catenin signaling has recently been shown to contribute to hypertensive arterial remodeling [45]. Contrary to our expectations, C1qa levels were decreased in our FR placentas, again highlighting the inconsistencies of whether cellular protective mechanisms are impaired or enhanced in response to adverse environments in these pathologic conditions of pregnancy.…”

Novel mechanisms and functions of complement

“…Since aberrant Wnt signaling is implicated in cancer and other degenerative diseases 75 , complement components may promote Wnt-dependent degenerative phenotypes during aging. In support of this notion, C1q was shown to promote hypertension-induced arterial remodeling through enhanced β-catenin signaling and aberrant proliferation of vascular smooth muscle cells 76 . Interestingly, complement downmodulates the expression of Klotho, a transmembrane co-receptor for FGF signaling that exerts pleiotropic anti-aging functions in various tissues 77 .…”

C1q, antibodies and anti-C1q autoantibodies

“…For example, C1q has been reported to play an important role in nerve pruning (Stevens et al, 2007) Wnt/Beta-catenin signalling (Naito et al, 2012;Sumida et al, 2015). Also a role for C1q was reported on neoangiogenesis (Bossi et al, 2014).…”