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.
Highlights
The endothelium forms a critical semi-permeable barrier between tissues and the bloodstream, regulating the transport of solutes and immune cells into and out of the circulation
To assess a potential role for the Abl kinases in the regulation of endothelial barrier function, we initially evaluated Abl kinase activity following treatment of human microvascular endothelial cells (HMVECs) with the permeability-inducing factors vascular endothelial growth factor (VEGF), thrombin, and histamine
In agreement with previous findings in human umbilical vein endothelial cells (HUVECs) [28,30,31], stimulation of HMVECs with VEGF resulted in Abl kinase activation, as assessed by the phosphorylation of CrkL at tyrosine (Y) 207, an Abl-specific phosphorylation site [32] (Figure 1A), which was prevented by pre-treatment with the ATP-competitive Abl kinase inhibitor imatinib
Summary
The endothelium forms a critical semi-permeable barrier between tissues and the bloodstream, regulating the transport of solutes and immune cells into and out of the circulation. The maintenance of this barrier is a dynamic and tightly-controlled process. Abnormally elevated vascular permeability is a key feature of a variety of pathological conditions, including cancer, sepsis, and ischemia-reperfusion injury [3,4]. This uncontrolled vascular leakage can lead to edema, increased interstitial fluid pressure, and tissue damage [4]. Dimerization and clustering of VE-cadherin at sites of endothelial cell-cell contact leads to homotypic, Ca2+-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
