Abstract 8885: C1q-induced Activation of Wnt Signaling Triggers Hypertensive Arterial Remodeling

Abstract

Hypertension is the leading risk factor of many cardiovascular diseases, and the structural remodeling of arteries in response to elevated blood pressure (hypertensive arterial remodeling) contributes to the end-organ damage associated with hypertension. The signaling mechanism that initiates hypertensive arterial remodeling remains elusive. Here we show that complement C1q-induced activation of Wnt signaling plays a critical role in arterial remodeling associated with hypertension. In the early phase of hypertension, proliferation of vascular smooth muscle cells (VSMCs) and activation of canonical Wnt signaling in VSMCs were observed, and inhibition of canonical Wnt signaling suppressed hypertension-induced VSMC proliferation. Complement C1q was highly expressed in macrophages recruited to the vessel wall following blood pressure elevation, and depletion of macrophages attenuated hypertension-induced VSMC proliferation and activation of canonical Wnt signaling in VSMCs. Furthermore, both C1s inhibition and C1qa gene deletion suppressed activation of canonical Wnt signaling in VSMCs and VSMC proliferation in the early phase of hypertension, and prevented subsequent structural arterial remodeling in the chronic phase. Our findings collectively suggest that macrophage-derived C1q triggers hypertensive arterial remodeling through activation of canonical Wnt signaling in VSMCs. Inhibition of C1q-induced Wnt signal activation may be a novel therapeutic strategy to reduce cardiovascular complications in patients with hypertension.