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Yan Xiong,
Zhenqian Hu,
Xiaofan Han,
Beibei Jiang,
Rongli Zhang,
Xiaoyu Zhang, Yao Lu,
Chenyang Geng,
Wei Li,
Yulong He,
Yingqing Huo,
Masabumi Shibuya,
Jincai Luo
[show abstract]
[hide abstract]
ABSTRACT: Regulated endothelial exocytosis of Weibel-Palade bodies (WPBs), the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflammation, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells (ECs) through VEGF receptor 2 (VEGFR2) signaling pathways. Stretch triggers a rapid release (within minutes) of von Willebrand factor and interleukin-8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane. We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCγ1/calcium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic targets in limiting hypertensive stretch-related inflammation.Cell Research advance online publication 23 April 2013; doi:10.1038/cr.2013.56.
Cell Research 04/2013; · 8.19 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Vascular endothelial growth factor (VEGF) is best known as an angiogenic factor essential for embryonic vasculogenesis and postnatal angiogenesis. Considerable evidence has accumulated that VEGF also has non-angiogenic functions. Early studies demonstrated that VEGF transcripts are ubiquitously expressed, and the phosphorylation of VEGF receptor is detectable in adult organs that have no feature of angiogenesis. Recent clinical studies showed that the inhibition of VEGF signaling results in diverse angiogenesis-irrelevant side effects involving the dysfunctions of many organs, suggesting non-angiogenic roles of VEGF in the regulation of organ homeostasis. On the other hand, VEGF stimulates endothelial cells (ECs) to express intercellular adhesion molecules that mediate physical interactions with adjacent tissue cells, or secreted various multifunctional substances that affect the functions of surrounding organs. Furthermore, very recent studies including ours have revealed VEGF as a potent agonist for endothelial exocytosis of Weibel-Palade bodies in which thrombogenic and inflammatory factors are stored. In this brief review, we highlight the importance of VEGF non-angiogenic functions in the modulation of tissue repair and organ regeneration, vascular homeostasis, and inflammation, and propose that the non-angiogenic functions are primarily mediated through the substances released from ECs.
Journal of Molecular Medicine 03/2011; 89(7):635-45. · 4.67 Impact Factor
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Yao Lu,
Yan Xiong,
Yingqing Huo,
Jingyan Han,
Xiao Yang,
Rongli Zhang,
De-Sheng Zhu,
Stefan Klein-Heßling,
Jun Li,
Xiaoyu Zhang,
Xiaofan Han,
Yanli Li,
Bin Shen,
Yulong He,
Masabumi Shibuya,
Gen-Sheng Feng,
Jincai Luo
[show abstract]
[hide abstract]
ABSTRACT: The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that
Grb-2–associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium-specific Gab1
KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel
plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells
(ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses
revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1-deficient vessels and ECs following VEGF stimulation.
Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient
vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA
rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs
revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1
as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA.
Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable
potential in treatment of human ischemic diseases.
Proceedings of the National Academy of Sciences 02/2011; 108(7):2957-2962. · 9.68 Impact Factor
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Yao Lu,
Yan Xiong,
Yingqing Huo,
Jingyan Han,
Xiao Yang,
Rongli Zhang,
De-Sheng Zhu,
Stefan Klein-Hessling,
Jun Li,
Xiaoyu Zhang,
Xiaofan Han,
Yanli Li,
Bin Shen,
Yulong He,
Masabumi Shibuya,
Gen-Sheng Feng,
Jincai Luo
[show abstract]
[hide abstract]
ABSTRACT: The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that Grb-2-associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium-specific Gab1 KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells (ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1-deficient vessels and ECs following VEGF stimulation. Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1 as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA. Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable potential in treatment of human ischemic diseases.
Proceedings of the National Academy of Sciences 02/2011; 108(7):2957-62. · 9.68 Impact Factor
