Topic 3

Regulation of Endothelial Cell Survival and Vascular Function by ABL Kinases

Disruption of vascular function is implicated in diverse pathological conditions and is often associated with aberrant angiogenesis and/or altered vascular barrier function. Angiogenesis and vascular function are regulated by the binding of diverse growth factors to their cognate receptor tyrosine kinases. Among these are the angiopoietins (Angpt), which activate the Tie2 receptor tyrosine kinase in endothelial cells. We have uncovered novel roles for the Abl family kinases, Abl and Arg, in the regulation of vascular function in vitro and in mice and have identified the Abl kinases as regulators of Tie2 expression and signaling. Unexpectedly, we found that mice lacking Abl kinases in the endothelium exhibit perinatal lethality, revealing a critical requirement for Abl kinases in vascular development and function (Chislock et al. 2013, PNAS vol. 110: 12432-7). We found that Abl kinases are activated by several angiogenic factors, including Angpt1, and that pharmacological inhibition or depletion of Abl kinases in endothelial cells impairs cell survival in vitro and in mice (Figure 1).

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Fig. 1 – Loss of Abl kinases in endothelial cells results in increased apoptosis and decreased vascular density during embryonic development.  Pictured are regions of apoptosis and vascular abnormalities in the liver of a mouse embryo lacking expression of the Abl and Arg kinases in endothelial cells. Endothelial cells are shown in magenta and nuclei in blue. Cleaved caspase-3, a marker of apoptosis, is shown in green. Image courtesy of Elizabeth Chislock.

Notably, we uncovered a new signaling network linking Abl kinases to Tie2 in endothelial cells. Loss of Abl kinases resulted in a profound decrease in Tie2 expression and impaired Angpt1-Tie2-dependent signaling and endothelial cell survival. These studies have revealed a positive feedback loop linking Tie2 to Abl kinases that promotes endothelial cell survival. Alterations in Angpt/Tie2 signaling have been implicated in tumor angiogenesis and other vascular disorders. Thus, future studies will examine whether the Tie2-Abl pathway can be therapeutically targeted in the treatment of pathological angiogenesis.