Abl family kinases regulate endothelial barrier function in vitro and in mice

Elizabeth M Chislock, Ann Marie Pendergast, Elizabeth M Chislock, Ann Marie Pendergast

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 Ca(2+) 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Abl kinases are activated following…
Figure 1. Abl kinases are activated following treatment with endothelial permeability-inducing factors.
(A) Assessment of Abl kinase activation, as determined by phospho-CrkL tyrosine (Y) 207 levels, following stimulation of serum-starved HMVECs with 100ng/mL VEGF for 5 minutes, with or without imatinib pre-treatment (10μM). pCrkL (Y207) levels (normalized to total CrkL) are quantified in the right panel, relative to levels in untreated (UT) cells. Data are presented as means +/- SD (n=7). (B) Evaluation of pCrkL (Y207) levels in HMVECs treated with VEGF, with or without su6656 pre-treatment (1μM). pCrkL levels (normalized to total CrkL) are quantified in the right panel, relative to levels in untreated (UT) cells. Data are presented as means +/- SD (n=2). (C) Evaluation of Abl kinase activation (pCrkL Y207) following treatment of HMVECs with thrombin (1U/mL, 5 minutes), with or without imatinib pre-treatment. pCrkL levels (normalized to total CrkL) are quantified in the right panel, relative to levels in untreated (UT) cells. Data are presented as means +/- SD (n=5). (D) Assessment of Abl kinase activation (pCrkL Y207) following stimulation of HMVECs with histamine (100μM, 5 minutes), with or without imatinib pre-treatment. pCrkL levels (normalized to total CrkL) are quantified in the right panel, relative to levels in untreated (UT) cells. Data are presented as means +/- SD (n=3). *P<0.05; **P<0.01; ***P<0.001.
Figure 2. Loss of Abl kinase function…
Figure 2. Loss of Abl kinase function decreased endothelial barrier dysfunction in vitro.
(A) Evaluation of endothelial monolayer permeability, as assessed by passage of fluorescein-labeled dextran (molecular weight 40kDa) through HMVEC monolayers grown on Transwells, following treatment with VEGF (100ng/mL) with or without imatinib pre-treatment (10μM). Data shown are mean fluorescence of samples collected from bottom Transwell chambers at the indicated times post-VEGF treatment, +/- SD of three replicates per treatment. Data are representative of 3 independent experiments. (B) Quantification of inhibition of endothelial monolayer permeability to fluorescein-labeled dextran by imatinib (10μM) or GNF-2 (15μM). Endothelial barrier dysfunction was induced by treatment of HMVECs with VEGF (100ng/mL, 120 minutes), thrombin (1U/mL, 30 minutes) or histamine (100μM, 60 minutes). Values are expressed relative to permeability induction in vehicle-treated cells (UT). Data are presented as means +/- SEM (n=3). (C) Quantification of VEGF-induced endothelial permeability of HMVECs expressing either control or Abl miRNAs, with or without re-expression of miRNA-resistant, wild-type murine Abl (mAbl-WT). Values are expressed relative to VEGF-induced permeability in control miRNA-expressing cells. Data are presented as means +/- SEM (n=3). (D) Assessment of Abl protein levels following miRNA expression in HMVECs, with or without re-expression of miRNA-resistant Abl. *P<0.05; **P<0.01; ***P<0.001.
Figure 3. Abl kinases are required for…
Figure 3. Abl kinases are required for VEGF-induced vascular permeability in vivo.
(A) Evaluation of vascular leakage of Evans blue dye in mice following intradermal injection of VEGF (100ng, 15 minutes) with or without concomitant treatment with imatinib or GNF-2 (15μM). Dye extravasation was normalized to tissue weight. Values are presented as means +/- SD (n=12). (B) Quantification of VEGF-induced dermal vascular leakage of Evans blue dye in AblECKO; Arg+/- (Ablflox/flox; Arg+/-; Tie2-Cre+/-) and age/sex-matched Arg+/- control mice (Ablflox/flox; Arg+/-; Tie2-Cre-/-). Dye extravasation was normalized to tissue weight. Values are presented as means +/- SD (Arg+/- controls, n=8; AblECKO; Arg+/-, n=6). *P<0.05; **P<0.01.
Figure 4. Abl kinase activity is required…
Figure 4. Abl kinase activity is required for VEGF- and thrombin-induced disruption of endothelial adherens junctions.
(A) Staining of HMVEC monolayers for the adherens junction marker VE-cadherin (green) following treatment with VEGF (100ng/mL, 30 minutes), with or without imatinib pre-treatment (10μM). (B) VE-cadherin staining (red) of HMVEC monolayers treated with thrombin (1U/mL, 5 minutes), +/- imatinib. (C) VE-cadherin staining (red) of VEGF or thrombin-treated HMVECs, with or without GNF-2 pre-treatment (15μM). VEGF and thrombin treatment induced formation of inter-endothelial cell gaps (arrows) and destabilization of endothelial cell-cell junctions (“zig-zag” VE-cadherin staining pattern, arrowheads), which were reduced by pre-treatment with Abl kinase inhibitors.
Figure 5. Loss of Abl kinase activity…
Figure 5. Loss of Abl kinase activity impaired MLC2 phosphorylation in response to endothelial permeability-inducing factors.
(A) Assessment of phospho-MLC2 serine (S) 19 levels in HMVECs following VEGF stimulation (100ng/mL, 5 minutes) with or without imatinib pre-treatment (10μM). pMLC2(S19) levels, normalized to total MLC2, are quantified in the right panel, relative to levels in untreated cells (UT). Data are presented as means +/- SD (n=7). (B) Evaluation of pMLC2(S19) levels in HMVECs expressing either control or Abl miRNAs following VEGF treatment. pMLC2(S19) levels, normalized to total MLC2, are quantified in the right panel, relative to levels in untreated control miRNA-expressing cells (UT). Data are presented as means +/- SD (n=3). (C) Assessment of pMLC2(S19) levels in thrombin-treated HMVECs (1U/mL, 2 minutes), with or without imatinib pre-treatment. pMLC2(S19) levels, normalized to total MLC2, are quantified in the right panel, relative to levels in untreated cells (UT). Data are presented as means +/- SD (n=4). *P<0.05; **P<0.01.
Figure 6. Abl kinase inhibition impaired Ca…
Figure 6. Abl kinase inhibition impaired Ca2+ mobilization by endothelial permeability-inducing factors.
(A-B) Quantification of intracellular Ca2+ levels in HMVECs stimulated with VEGF (100ng/mL) with or without (A) imatinib (10μM) or (B) GNF-2 (15μM) pre-treatment. Values are expressed as increases in intracellular Ca2+ levels, relative to levels in unstimulated cells. Arrows indicate timing of addition of permeability-inducing factors. Data are presented as means +/- SD of 35 cells per treatment and are representative of 3 independent experiments. (C) Quantification of inhibition of Ca2+ mobilization by imatinib or GNF-2. Values shown are maximum intracellular Ca2+ levels in HMVECs treated with VEGF, thrombin (1U/mL), or histamine (100µM) in the presence of Abl kinase inhibitors, relative to levels in vehicle-treated cells (UT). Data are presented as means +/- SEM (n=3). (D) Assessment of VEGF-mediated phosphorylation of PLCγ1 and VEGFR2 in HMVECs, with or without GNF-2 pre-treatment. (E-F) Quantification of levels of (E) phospho-PLCγ1 tyrosine (Y) 783 and (F) phospho-VEGFR2 Y1175 in HMVECs treated with VEGF +/- GNF-2, relative to levels in vehicle-treated cells (UT) at each time point. Data are presented as means +/- SD (n=3). *P<0.05; **P<0.01; ***P<0.001.
Figure 7. Model for the role of…
Figure 7. Model for the role of the Abl family kinases in signaling pathways regulating endothelial permeability.
The Abl and Arg kinases are activated in endothelial cells downstream of receptors for the permeability-inducing factors VEGF, thrombin, and histamine. VEGF-mediated Abl kinase activation requires Src family kinase activity. The Abl kinases positively regulate phosphorylation of MLC2 (S19) in response to these permeability-inducing agonists, likely through regulating the activity of Ca2+/calmodulin-dependent targets such as MLCK. Abl kinase activity is required for maximal Ca2+ mobilization in response to stimulation with permeability-inducing factors. The Abl kinases additionally modulate VEGF-induced phosphorylation of VEGFR2 at Y1175, which regulates downstream PLCγ activation, IP3 generation, and ER Ca2+ release. Abl kinases promote Ca2+ mobilization by thrombin and histamine by mechanisms yet to be characterized. Abl kinases negatively regulate basal activity levels of the Rac1 and Rap1 GTPases, which have been shown to support endothelial barrier function by promoting cortical actin deposition and adherens junction stability. Abbreviations: EC, endothelial cell; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; Y, tyrosine; PAR-1, protease-activated receptor 1 (thrombin); H1, histamine H1 receptor; MLC2, myosin regulatory light chain; S, serine; MLCK, myosin light chain kinase; PLC, phospholipase C; IP3, inositol-1,4,5-trisphosphate; IP3R, IP3 receptor; ER, endoplasmic reticulum.

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