The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis

Herkenne, Stéphanie; Paques, Cécile; Nivelles, Olivier; Lion, Michelle; Bajou, Khalid; Pollenus, Thomas; Fontaine, M.; Carmeliet, Peter; Martial, Joseph; Nguyen, Ngoc-Quynh-Nhu; Struman, Ingrid

doi:10.1126/scisignal.aaa2403

Cited by 47 publications

(34 citation statements)

References 75 publications

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“…To measure an effect of SH003 on the proliferation, human umbilical vascular endothelial cells (HUVECs) were treated with VEGF (50ng/ml) and different concentrations of SH003 (10, 20 or 50μg/ml) for 24 hours. While VEGF increased HUVEC proliferation rate as previously reported [38, 40], SH003 did not affect VEGF-induced HUVEC proliferation (Figure 1A). However, SH003 inhibited the number of VEGF-dependent migrated cells into the scratched region, when cells were treated with VEGF and SH003 for 9.5 hours (Figure 1B).…”

Section: Resultssupporting

confidence: 88%

SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2

et al. 2016

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Tumor angiogenesis is a key feature of cancer progression, because a tumor requires abundant oxygen and nutrition to grow. Here, we demonstrate that SH003, a mixed herbal extract containing Astragalus membranaceus (Am), Angelica gigas (Ag) and Trichosanthes Kirilowii Maximowicz (Tk), represses VEGF-induced tumor angiogenesis both in vitro and in vivo. SH003 inhibited VEGF-induced migration, invasion and tube formation in human umbilical vein endothelial cells (HUVEC) with no effect on the proliferation. SH003 reduced CD31-positive vessel numbers in tumor tissues and retarded tumor growth in our xenograft mouse tumor model, while SH003 did not affect pancreatic tumor cell viability. Consistently, SH003 inhibited VEGF-stimulated vascular permeability in ears and back skins. Moreover, SH003 inhibited VEGF-induced VEGFR2-dependent signaling by blocking VEGF binding to VEGFR2. Therefore, our data conclude that SH003 represses tumor angiogenesis by inhibiting VEGF-induced VEGFR2 activation, and suggest that SH003 may be useful for treating cancer.

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Section: Resultssupporting

confidence: 88%

SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2

et al. 2016

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“…Studies have shown that in mature vessels, autocrine expression of low levels of VEGF is essential for vessel homeostasis whereas high levels of VEGF induce branching angiogenesis [37]. Numerous studies that evaluated the efficacy of proangiogenic gene therapy suggested that VEGF is a critical factor in therapeutic angiogenesis [38–40]. DHI is widely used in the treatment of cardiovascular diseases such as acute myocardial infarction, coronary heart and so on [41,42] and the beneficial effects could be seen in experimental ischemia models [43].…”

Section: Discussionmentioning

confidence: 99%

Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice

Zhao

Guo

et al. 2016

PLoS ONE

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Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways.

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“…Low-density lipoprotein receptor-related protein-1 also forms a multireceptor complex with VEGFR2, β1-integrin, and uPAR on the cell membrane of ECs and targets this multiprotein complex for endocytosis (Mechanism #1 in Figure 2) (33). Upon VEGF treatment, LRP1 mediates the internalization of this protein complex into the cell.…”

Section: Lrp1 and Upar–upa–plasminogen Activator Inhibitor 1 (Pai-1) mentioning

confidence: 99%

Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis

Mao

Xie

2017

Front. Cardiovasc. Med.

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Low-density lipoprotein receptor-related protein-1 (LRP1) plays multifunctional roles in lipid homeostasis, signaling transduction, and endocytosis. It has been recognized as an endocytic receptor for many ligands and is involved in the signaling pathways of many growth factors or cytokines. Dysregulation of LRP1-dependent signaling events contributes to the development of pathophysiologic processes such as Alzheimer’s disease, atherosclerosis, inflammation, and coagulation. Interestingly, recent studies have linked LRP1 with endothelial function and angiogenesis, which has been underappreciated for a long time. During zebrafish embryonic development, LRP1 is required for the formation of vascular network, especially for the venous development. LRP1 depletion in the mouse embryo proper leads to angiogenic defects and disruption of endothelial integrity. Moreover, in a mouse oxygen-induced retinopathy model, specific depletion of LRP1 in endothelial cells results in abnormal development of neovessels. These loss-of-function studies suggest that LRP1 plays a pivotal role in angiogenesis. The review addresses the recent advances in the roles of LRP1-dependent signaling during angiogenesis.

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The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis

Abstract: uPAR enhances the internalization and thus the signaling downstream of a proangiogenic receptor.

Cited by 47 publications

References 75 publications

SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2

SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2

Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice

Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis

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