A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

Guo, Chengjun; Goodwin, Andrew; Buie, Joy N. Jones; Cook, James A.; Halushka, Perry V.; Argraves, Kelley M.; Zingarelli, Basilia; Zhang, Xian; Wang, Liping

doi:10.2119/molmed.2015.00240

Cited by 15 publications

(15 citation statements)

References 46 publications

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“…Thus, we performed post-treatment experiments and detected that activation of CXCR4 after thrombin-exposure of hPPAEC and HULEC5a cells attenuates thrombin-mediated impairment of lung endothelial barrier function. These findings support the concept that CXCR4 agonists have therapeutic potential to limit thrombin-mediated pulmonary vascular leakage, which likely contributed to lung protective effects of CXCR4 agonists that have been observed in various models when administered after the insult [ 15 , 17 , 18 , 21 , 43 ].…”

Section: Discussionsupporting

confidence: 80%

“…Furthermore, pre-treatment of bovine aortic endothelial cells with CXCL12 has been reported to attenuate thrombin-induced FITC-dextran transfer in transwell permeability assays. Likewise, co-treatment of human microvascular endothelial cells with CXCL12 or CTCE-0214, a synthetic CXCL12 analogue, plus thrombin attenuated the reduction of transendothelial resistance that was detectable with thrombin alone [ 15 , 22 ]. Our observations from the present study are in agreement with previous reports and now provide direct evidence that CXCL12 enhances barrier function of hPPAEC in the absence of permeability-inducing agents.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, administration of cognate, non-cognate and synthetic chemokine (C-X-C) motif receptor (CXCR) 4 agonists has been shown to attenuate lung injury in various experimental models and CXCL12 (stromal cell-derived factor-1α), the cognate agonist of CXCR4 and atypical chemokine receptor 3 (ACKR3), has been described to attenuate thrombin-induced impairment of endothelial cell barrier function [ 15 – 22 ]. A more detailed pharmacological characterization of these CXCL12-mediated effects, however, is lacking and the effects of other CXCR4/ACKR3 ligands on lung endothelial cell barrier function are ill defined.…”

Section: Introductionmentioning

confidence: 99%

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Effects of cognate, non-cognate and synthetic CXCR4 and ACKR3 ligands on human lung endothelial cell barrier function

et al. 2017

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Recent evidence suggests that chemokine CXCL12, the cognate agonist of chemokine receptors CXCR4 and ACKR3, reduces thrombin-mediated impairment of endothelial barrier function. A detailed characterization of the effects of CXCL12 on thrombin-mediated human lung endothelial hyperpermeability is lacking and structure-function correlations are not available. Furthermore, effects of other CXCR4/ACKR3 ligands on lung endothelial barrier function are unknown. Thus, we tested the effects of a panel of CXCR4/ACKR3 ligands (CXCL12, CXCL11, ubiquitin, AMD3100, TC14012) and compared the CXCR4/ACKR3 activities of CXCL12 variants (CXCL12α/β, CXCL12(3–68), CXCL121, CXCL122, CXCL12-S-S4V, CXCL12-R47E, CXCL12-K27A/R41A/R47A) with their effects on human lung endothelial barrier function in permeability assays. CXCL12α enhanced human primary pulmonary artery endothelial cell (hPPAEC) barrier function, whereas CXCL11, ubiquitin, AMD3100 and TC14012 were ineffective. Pre-treatment of hPPAEC with CXCL12α and ubiquitin reduced thrombin-mediated hyperpermeability. CXCL12α-treatment of hPPAEC after thrombin exposure reduced barrier function impairment by 70% (EC50 0.05–0.5nM), which could be antagonized with AMD3100; ubiquitin (0.03–3μM) was ineffective. In a human lung microvascular endothelial cell line (HULEC5a), CXCL12α and ubiquitin post-treatment attenuated thrombin-induced hyperpermeability to a similar degree. CXCL12(3–68) was inefficient to activate CXCR4 in Presto-Tango β-arrestin2 recruitment assays; CXCL12-S-S4V, CXCL12-R47E and CXCL12-K27A/R41A/R47A showed significantly reduced potencies to activate CXCR4. While the potencies of all proteins in ACKR3 Presto-Tango assays were comparable, the efficacy of CXCL12(3–68) to activate ACKR3 was significantly reduced. The potencies to attenuate thrombin-mediated hPPAEC barrier function impairment were: CXCL12α/β, CXCL121, CXCL12-K27A/R41A/R47A > CXCL12-S-S4V, CXCL12-R47E > CXCL122 > CXCL12(3–68). Our findings indicate that CXCR4 activation attenuates thrombin-induced lung endothelial barrier function impairment and suggest that protective effects of CXCL12 are dictated by its CXCR4 agonist activity and interactions of distinct protein moieties with heparan sulfate on the endothelial surface. These data may facilitate development of compounds with improved pharmacological properties to attenuate thrombin-induced vascular leakage in the pulmonary circulation.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of cognate, non-cognate and synthetic CXCR4 and ACKR3 ligands on human lung endothelial cell barrier function

et al. 2017

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“…36,37 We found that the CXCL12/CXCR4 axis reduces endothelial permeability through Akt/WNT- and VE-cadherin-mediated mechanisms, which may refine and underlie findings that CXCL12 or its analogs can reduce thrombin-induced endothelial permeability and pulmonary vascular leakage in a model of LPS-induced acute respiratory distress syndrome. 38,39 Notably extending previous findings 23 , stabilizing the interaction between VE-cadherin and VE-PTP prevented the impairment of endothelial barrier function upon interference with CXCR4. Surprisingly, atherosclerosis-prone endothelium displays increased β-catenin nuclear localization.…”

Section: Discussionsupporting

confidence: 78%

“…Owing to interference with the role of CXCR4 in progenitor cell mobilization and trafficking, systemic approaches, e.g. using non-cleavable CXCL12 peptides 39 or small molecule agonists to boost CXCR4 function, carry a substantial risk of side effects and suboptimal efficacy, e.g. due to pro-atherogenic effects of CXCR4-bearing BM-derived cells.…”

Section: Discussionmentioning

confidence: 99%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

147

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Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

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Role of microRNAs in sepsis

Kingsley

Bhat

2017

Inflamm. Res.

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A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

Cited by 15 publications

References 46 publications

Effects of cognate, non-cognate and synthetic CXCR4 and ACKR3 ligands on human lung endothelial cell barrier function

Effects of cognate, non-cognate and synthetic CXCR4 and ACKR3 ligands on human lung endothelial cell barrier function

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Role of microRNAs in sepsis

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