Grb-2–associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A–endothelial NOS pathway

Lu, Yingru; Xiong, Yan; Huo, Yingqing; Han, Jing‐Yan; Yang, Xiao; Zhang, Rongli; Zhu, Daling; Klein-Heßling, Stefan; Li, Jun; Zhang, Xiaoyu; Han, Xiaofan; Li, Yanli; Shen, Bin; He, Yulong; Shibuya, Masabumi; Feng, Gen‐Sheng; Luo, Jincai

doi:10.1073/pnas.1009395108

Cited by 64 publications

(61 citation statements)

References 26 publications

(43 reference statements)

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“…Rabbit polyclonal antibodies to phospho-PKC substrate and phospho-Akt (Ser 473 ) (for detecting Akt activation) were from Cell Signaling Technology (Beverly, MA, USA). Rabbit antisera against p85, VEGFR1 and VEGFR2 were obtained as previously described [32]. In the signaling experiments, p85 was mostly used as the loading control, as we found that general loading controls such as GAPDH, tubulin and actin were too abundant to accurately reflect protein loading in lysates.…”

Section: Reagentsmentioning

confidence: 99%

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Xiong

Han

et al. 2013

Cell Res

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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.

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Section: Reagentsmentioning

confidence: 99%

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Xiong

Han

et al. 2013

Cell Res

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“…Our group and others have demonstrated that endothelial-specific Gab1 deficiency in mice impairs ischemia-induced angiogenesis. [16][17][18] Moreover, in contrast to the defects in cardiac development observed in Gab1 − / − mice, cardiomyocyte-specific Gab1 conditional knockout (Gab1-cKO) mice generated with the Cre-LoxP system are viable and display normal cardiac morphology at birth. 19 Gab protein family has three members, Gab1, Gab2 and Gab3.…”

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confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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“…5 This finding is in agreement with another report showing that Gab1 is involved in ischemic and VEGF-induced angiogenesis using the same strategy for endothelial deletion of Gab1. 6 A third study using the Gab1ECKO mouse model further confirmed the requirement of Gab1 for postnatal angiogenesis. 7 In the present study, 1 the Komuro group moved from the HLI model to an experimental setting modeling vascular inflammation and atherosclerosis.…”

Section: Article P 2031mentioning

confidence: 73%

The Versatile Role of Gab1 in the Circulatory System

Wöhrle

Halbach

Brummer

2012

Circ J

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Grb-2–associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A–endothelial NOS pathway

Cited by 64 publications

References 26 publications

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

The Versatile Role of Gab1 in the Circulatory System

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