WNK1 collaborates with TGF-β in endothelial cell junction turnover and angiogenesis

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Abstract
Angiogenesis is essential for growth of new blood vessels, remodeling existing vessels, and repair of damaged vessels, and these require reorganization of endothelial cell–cell junctions through a partial endothelial–mesenchymal transition. Homozygous disruption of the gene encoding the protein kinase WNK1 results in lethality in mice near embryonic day (E) 12 due to impaired angiogenesis. This angiogenesis defect can be rescued by endothelial-specific expression of an activated form of the WNK1 substrate kinase OSR1. We show that inhibition of WNK1 kinase activity not only prevents sprouting of endothelial cells from aortic slices but also vessel extension in inhibitor-treated embryos ex vivo. Mutations affecting TGF-β signaling also result in abnormal vascular development beginning by E10 and, ultimately, embryonic lethality. Previously, we demonstrated cross-talk of WNK1 with TGF-β–regulated SMAD signaling, and OSR1 was identified as a component of the TGF-β interactome. However, molecular events jointly regulated by TGF-β and WNK1/OSR1 have not been delineated. Here, we show that inhibition of WNK1 promotes TGF-β–dependent degradation of the tyrosine kinase receptor AXL, which is involved in TGF-β–mediated cell migration and angiogenesis. We also show that interaction between OSR1 and occludin, a protein associated with endothelial tight junctions, is an essential step to enable tight junction turnover. Furthermore, we show that these phenomena are WNK1 dependent, and sensitive to TGF-β. These findings demonstrate intimate connections between WNK1/OSR1 and multiple TGF-β–sensitive molecules controlling angiogenesis and suggest that WNK1 may modulate many TGF-β–regulated functions.
Funding Information
  • HHS | NIH | National Heart, Lung, and Blood Institute (NIH R01 HL147661)
  • American Heart Association (18POST34030438)
  • Welch Foundation (I1243)
  • Welch Foundation (I1128)
  • Cancer Prevention and Research Institute of Texas (RP190421)
  • Mary Kay Ash Foundation (18-18)
  • Cancer Prevention and Research Institute of Texas (RP160157)
  • HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK110358)
  • HHS | NIH | National Heart, Lung, and Blood Institute (HL126518)

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