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Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease
- Source :
- Journal of Clinical Investigation. May 15, 2024, Vol. 134 Issue 10
- Publication Year :
- 2024
-
Abstract
- Clarkson disease, or 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. The 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 was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability- inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of W(y)-nitro-L-arginine methyl ester (L-NAME) ameliorated 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 hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.<br />Introduction The initial presentation of Clarkson disease, or monoclonal gammopathy- associated idiopathic systemic capillary leak syndrome (ISCLS), is frequently complicated by multiple organ dysfunction syndrome (MODS), rhabdomyolysis, and intravascular thrombosis [...]
- Subjects :
- Rare diseases -- Risk factors -- Development and progression -- Models
Vascular endothelium -- Physiological aspects -- Health aspects
Inflammation -- Complications and side effects
Blood circulation disorders -- Models -- Risk factors -- Development and progression
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 10
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.795617134
- Full Text :
- https://doi.org/10.1172/JCI169137