Intrinsic endothelial hyper-responsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. Specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here we characterize an autonomous vascular endothelial defect in ISCLS that is recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs are functionally hyper-responsive to permeability-inducing factors like VEGF and histamine in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-L-arginine methyl ester (L-NAME) ameliorates vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyper-activation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.