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. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing (scRNA-seq). Increased expression of CCN1 and CCN2 were discovered and further confirmed in APS skin by microscopy, and in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered CCN1 and CCN2 upregulation via yes-associated protein (YAP1)-mediated signaling. CCN2 originating from APS IgG-stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, which were blocked by the anti-CCN2 antibody, pamrevlumab. We further observed increased expression of CCN1 and CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with pamrevlumab significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG-accelerated neointima formation. Together, this study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and VSMCs. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy and provide potential therapeutic targets for patients.