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Originally published online as doi:10.2353/ajpath.2009.090094 on July 30, 2009

Published online before print July 30, 2009
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(American Journal of Pathology. 2009;175:1315-1327.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090094

Endothelial-Specific Expression of WNK1 Kinase Is Essential for Angiogenesis and Heart Development in Mice

Jian Xie*, Tao Wu*, Ke Xu{dagger}, Ivan K. Huang*, Ondine Cleaver{dagger} and Chou-Long Huang*

From the Departments of Medicine* and Molecular Biology,{dagger} University of Texas Southwestern Medical Center, Dallas, Texas

WNK1 [with-no-lysine (K)–1] is a ubiquitous serine/threonine kinase with a unique placement of the catalytic lysine residue. Increased WNK1 expression levels in humans causes a hypertension-hyperkalemia syndrome by altering renal Na+ and K+ transport. The function of WNK1 outside of the kidney remains elusive. In this study, we report that Wnk1 ablation causes cardiovascular developmental defects. The developing heart of null mutant embryos has smaller chambers and reduced myocardial trabeculation at E10.5. Yolk sac vessels in the E10.5 null mutant fail to remodel into a network of large and small vessels, and embryonic vessels show defective angiogenesis that involves both arteries and veins. The arterial marker neuropilin-1 and venous marker EphB4 are ectopically expressed in mutant veins and arteries, respectively. However, the orphan nuclear receptor COUP-TFII as well as the Notch signaling pathway, which are known to be critical for angiogenesis and artery-vein specification, are not significantly altered in Wnk1–/– mutants. Conditional deletion of Wnk1 in endothelial cells phenotypically copies defects caused by global Wnk1 ablation. Moreover, endothelial-specific expression of a Wnk1 transgene rescues cardiovascular developmental defects in Wnk1–/– mice. These findings identify a novel function of WNK1 in endothelial cells that is critical for angiogenesis and heart development, raising the possibility for a role of endothelial WNK1 in the control of blood pressure and postnatal angiogenesis and cardiac growth.


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