Microvascular endothelial cells license APS vasculopathy through YAP1- and CCN2-mediated signaling

Antiphospholipid syndrome (APS)-associated vasculopathy is heralded by abnormal proliferation of endothelial and smooth muscle cells, leading to small blood vessel occlusion in the skin, kidneys, and heart, amongst other organs. Skin biopsies of patients with APS demonstrated upregulation of CCN1 and CCN2 gene transcription in microvascular endothelial cells (MVECs). Increased CCN1 and CCN2 were confirmed in APS skin by microscopy and in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG induced CCN1 and CCN2 upregulation via yes-associated protein (YAP1)-mediated signaling. CCN2 originating from APS IgG-stimulated MVECs triggered the proliferation and migration of vascular smooth muscle cells, which could be blocked by the anti-CCN2 antibody pamrevlumab. Finally, we observed increased expression of CCN1 and CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Together, these findings offer insights into the molecular mechanisms underlying APS vasculopathy and provide potential therapeutic targets for patients.