Endogenous Vascular Endothelial Growth Factor-A (VEGF-A) Maintains Endothelial Cell Homeostasis by Regulating VEGF Receptor-2 Transcription

Guangqi, E; Cao, Ying; Bhattacharya, Santanu; Dutta, Shamit K.; Wang, Enfeng; Mukhopadhyay, Debabrata

doi:10.1074/jbc.m111.293985

Cited by 51 publications

(17 citation statements)

References 60 publications

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“…Consistent with findings from a recent report [23], a complex of endogenous VEGF and VEGFR2 also exists in quiescent HCAECs. More importantly, a significant increase (33.5%; P < 0.0001) in VEGF-VEGFR2 association is detected as early as 15 s after the onset of flow (Fig.…”

Section: Resultssupporting

confidence: 93%

Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity

Paz

Melchior

Frangos

2013

Biochemical and Biophysical Research Communications

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Although several potential mechanosensors/mechanotransducers have been proposed, the precise mechanisms by which ECs sense and respond to mechanical forces and translate them into biochemical signals remains unclear. Here, we report that two major ligand-dependent tyrosine autophosphorylation sites of VEGFR2, Y1175 and Y1214, are rapidly activated by shear stress in human coronary artery endothelial cells (HCAECs). Neutralizing antibody against VEGFR2 not only abrogates flow-induced phosphorylation of these tyrosine residues, but also has a marked inhibitory effect on downstream eNOS activation. In situ proximity ligation assay revealed that VEGF and VEGFR2 are closely associated in HCAECs, and more importantly, this association is increased with flow. Finally, we show that flow-induced VEGFR2 activation is attenuated in the presence of the broad spectrum matrix metalloproteinase (MMP) inhibitor, GM6001. Taken together, our results suggest that a ligand-dependent mechanism involving the activity of MMPs plays a key role in the early, shear stress-induced activation of VEGFR2.

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Section: Resultssupporting

confidence: 93%

Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity

Paz

Melchior

Frangos

2013

Biochemical and Biophysical Research Communications

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“…This novel in vivo finding extends our understanding regarding the role of VEGF in tumorigenesis, which may translate into modified cancer treatments in the near future. Furthermore, our recent research results showed that the way of autocrine/endogenesis VEGF acting in the cells differed from the paracrine/exogenous VEGF (20). The paracrine VEGF can be more easily blocked by the antibodies than the autocrine VEGF.…”

Section: Resultsmentioning

confidence: 99%

VEGF Exerts an Angiogenesis-Independent Function in Cancer Cells to Promote Their Malignant Progression

et al. 2012

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Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF or VEGF-A) is a pivotal driver of cancer angiogenesis that is a central therapeutic target in treatment of malignancy. However, little work has been devoted to investigating functions of VEGF that are independent of its pro-angiogenic activity. Here we report that VEGF produced by tumor cells acts in an autocrine manner to promote cell growth through interaction with the VEGF receptor neuropilin-1 (NRP-1). Reducing VEGF expression by tumor cells induced a differentiated phenotype in vitro and inhibited tumor-forming capacity in vivo independent of effects on angiogenesis. Autocrine activation of tumor cell growth was dependent on signaling through NRP-1 and Ras was determined to a critical effector signaling molecule downstream of NRP-1. Our findings define a novel function for VEGF in de-differentiation of tumor cells, expanding its role in cancer beyond its known pro-angiogenic function.

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“…Recent studies revealed that VEGF secreted by endothelial cells are functionally different from VEGF secreted by astrocytes 7 . Endothelial cell-derived VEGF maintains endothelial homeostasis 8 and vascular homeostasis 9 . Endothelial cell-specific deletion of VEGF clearly inhibited human umbilical vein endothelial cells (HUVECs) tube formation 8 .…”

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confidence: 99%

MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1

Mao

Gao

et al. 2015

Sci Rep

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Previous studies have suggested that microRNA-107 (miR-107) regulates cell migration in tumor and promotes Hypoxia Inducible Factor 1α (HIF1α) regulated angiogenesis under hypoxia. We found that miR-107 was strongly expressed in ischemic boundary zone (IBZ) after permanent middle cerebral artery occlusion (pMCAO) in rats and inhibition of miR-107 could reduce capillary density in the IBZ after stroke. Such finding led us to hypothesize that miR-107 might regulate post-stroke angiogenesis and therefore serve as a therapeutic target. We also found that antagomir-107, a synthetic miR-107 inhibitor, decreased the number of capillaries in IBZ and increased overall infarct volume after pMCAO in rats. We demonstrated that miR-107 could directly down-regulate Dicer-1, a gene that encodes an enzyme essential for processing microRNA (miRNA) precursors. This resulted in translational desupression of VEGF (vascular endothelial growth factor) mRNA, thereby increasing expression of endothelial cell-derived VEGF (VEGF165/VEGF164), leading to angiogenesis after stroke. This process might be a protective mechanism for ischemia-induced cerebral injury and miR-107 might be used as a novel tool in stroke treatment.

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Endogenous Vascular Endothelial Growth Factor-A (VEGF-A) Maintains Endothelial Cell Homeostasis by Regulating VEGF Receptor-2 Transcription

Cited by 51 publications

References 60 publications

Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity

Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity

VEGF Exerts an Angiogenesis-Independent Function in Cancer Cells to Promote Their Malignant Progression

MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1

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