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ResearchIn-Press PreviewVascular biology Open Access | 10.1172/JCI169137
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Ablooglu, A. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Chen, W. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Xie, Z. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Desai, A. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Paul, S. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Lack, J. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Scott, L. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Eisch, A. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Dudek, A. in: JCI | PubMed | Google Scholar
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Parikh, S. in: JCI | PubMed | Google Scholar |
1Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, United States of America
2Integrative Data Sciences Section, NIAID/NIH, Bethesda, United States of America
3Division of Medical Oncology, Mayo Clinic, Rochester, United States of America
4Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, United States of America
Find articles by Druey, K. in: JCI | PubMed | Google Scholar
Published March 19, 2024 - More info
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.