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The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from revers-ible microvascular barrier dysfunction. Although the high prevalence of a mono-clonal gammopathy of unknown signifi-cance in SCLS suggests a pathogenic contribution of endogenous immuno-globulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of epi-sodic SCLS sera, but neither the purified immunoglobulin fraction nor sera ob-talned from patients during remission, to human microvascular endothelial cells caused vascular endothelial Cadherin in-ternalization, disruption of interendothe-lial junctions, actin stress fiber formation, and increased permeability in comple-mentary functional assays without induc-ing endothelial apoptosis. Intravenous Im-munoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the pres-ence of endogenous, nonimmunoglobu-lln, circulating permeability factor(s) con-strained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and anglopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remis-sion sera. Ab-based inhibition of Ang2 counteracted permeability induced by ep-isodic SCLS sera. Comparable experi-ments with anti-VEGF Ab (bevacizumab) yielded less interpretable results, prob-ably because of endothelial toxicity of VEGF withdrawal. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a mo-lecular mechanism for this highly lethal disorder. (Blood. 2012;119(18):4321-4332) [ABSTRACT FROM AUTHOR]