Abl Family Kinases Regulate Endothelial Barrier Function In Vitro and in Mice

Abstract

The maintenance of endothelial barrier function is essential for normal physiology, and increased vascular permeability is a feature of a wide variety of pathological conditions, leading to complications including edema and tissue damage. Use of the pharmacological inhibitor imatinib, which targets the Abl family of non-receptor tyrosine kinases (Abl and Arg), as well as other tyrosine kinases including the platelet-derived growth factor receptor (PDGFR), Kit, colony stimulating factor 1 receptor (CSF1R), and discoidin domain receptors, has shown protective effects in animal models of inflammation, sepsis, and other pathologies characterized by enhanced vascular permeability. However, the imatinib targets involved in modulation of vascular permeability have not been well-characterized, as imatinib inhibits multiple tyrosine kinases not only in endothelial cells and pericytes but also immune cells important for disorders associated with pathological inflammation and abnormal vascular permeability. In this work we employ endothelial Abl knockout mice to show for the first time a direct role for Abl in the regulation of vascular permeability in vivo. Using both Abl/Arg-specific pharmacological inhibition and endothelial Abl knockout mice, we demonstrate a requirement for Abl kinase activity in the induction of endothelial permeability by vascular endothelial growth factor both in vitro and in vivo. Notably, Abl kinase inhibition also impaired endothelial permeability in response to the inflammatory mediators thrombin and histamine. Mechanistically, we show that loss of Abl kinase activity was accompanied by activation of the barrier-stabilizing GTPases Rac1 and Rap1, as well as inhibition of agonist-induced Ca2+ mobilization and generation of acto-myosin contractility. In all, these findings suggest that pharmacological targeting of the Abl kinases may be capable of inhibiting endothelial permeability induced by a broad range of agonists and that use of Abl kinase inhibitors may have potential for the treatment of disorders involving pathological vascular leakage.

The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions

“…Recent studies have identified roles for members of the ABL family of non-receptor tyrosine kinases (ABL1 and ARG) and RhoA and ROCK in histamine-induced VE leakage; therefore, we examined histamine and IL-4C induction of ABL1 kinase activity 15, 52 . Employing the immortalized human endothelial cell line (EA.hy926), we firstly examined ABL1 kinase activity after histamine and IL-4C stimulation.…”

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

“…Previous studies have suggested differential roles for the Abl family kinases, c-Abl and Arg, in mediating EC barrier function (2,11). Because imatinib inhibits both these kinases, siRNA technology was employed to individually downregulate the expression of c-Abl or Arg in HPAEC to investigate the specific functions of c-Abl and Arg in our models of EC dysfunction.…”

Endothelial barrier dysfunction, loss of microcirculatory flow and organ failure in sepsis: current clinical view of sepsis and links to basic research

“…Some clinical trials showed an association of Imatinib treatment with resolution of edema (59)(60) (61). Preclinical trials demonstrated that Imatinib reduces edema via preservation of endothelial barrier integrity (62) (63). Inhibition of Abl kinase activity causes an activation of Rac1 and Rap1 and thereby a stabilization of endothelial barrier, as mentioned before.…”