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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Vascular dysfunction in the alpha-galactosidase A-knockout mouse is an endothelial cell-, plasma membrane-based
James L Park1, Steven E Whitesall, Louis G D'Alecy
1Division of Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Clinical and Experimental Pharmacology & Physiology
|June 21, 2008
Summary
Fabry disease impairs vascular smooth muscle function due to globotriaosylceramide (Gb3) accumulation. This study reveals the vasculopathy is localized to the endothelium, not the smooth muscle, impacting vascular reactivity.
Area of Science:
- Cardiovascular Biology
- Lysosomal Storage Diseases
- Genetics
Background:
- Fabry disease, an X-linked disorder, stems from alpha-galactosidase A (Gla) deficiency, leading to glycosphingolipid (GSL) buildup.
- Accumulation of globotriaosylceramide (Gb3) in vascular endothelium contributes to thrombosis, atherogenesis, and endothelial dysfunction.
- The precise mechanisms underlying endothelial dysfunction in Fabry disease remain incompletely understood.
Purpose of the Study:
- To investigate the specific vasculopathy in a murine model of Fabry disease.
- To characterize alterations in vascular reactivity and blood pressure regulation in Gla-knockout mice.
Main Methods:
- Vascular reactivity assays were conducted on isolated vessels from wild-type and Gla-knockout mice.
- Telemetric measurements of conscious blood pressure and heart rate were performed.
- Vascular smooth muscle (VSM) and endothelium-dependent responses were assessed.
Main Results:
- Gla-knockout mice exhibited blunted VSM contractions to phenylephrine and serotonin, but not U46619.
- Endothelium-dependent contraction and acetylcholine-induced relaxation were significantly attenuated.
- Endothelium-dependent relaxation to ionomycin remained intact, and VSM reactivity was normal without endothelium.
Conclusions:
- The vasculopathy in Fabry disease is primarily localized to the endothelium, despite widespread GSL accumulation.
- Endothelial dysfunction, rather than direct smooth muscle impairment, drives vascular abnormalities in this condition.
- These findings highlight the critical role of the endothelium in Fabry disease pathogenesis.
