“Decoding” Angiogenesis: New Facets Controlling Endothelial Cell Behavior

Sewduth, Raj Nayan; Santoro, Massimo

doi:10.3389/fphys.2016.00306

Cited by 35 publications

(15 citation statements)

References 67 publications

(90 reference statements)

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“…Our study clearly demonstrates that VEGFi induces a change in microparticles to a pro-inflammatory phenotype as evidenced by the significant increase in expression of endothelial pro-inflammatory mediators including IL-6, TNF-α, MCP-1, Cox2, VCAM-1, and iNOS. Other studies have also shown that microparticles from various cell types including monocytes, platelets and endothelial cells, promote inflammation and apoptosis 52–58 . Some of these processes are mediated by ROS and, as we show, the ET-1 system may also be important.…”

Section: Discussionsupporting

confidence: 69%

Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Neves

Jones

Evans

et al. 2019

Cardiovascular Research

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Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (10 6 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO − levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy : our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.

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Section: Discussionsupporting

confidence: 69%

Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Neves

Jones

Evans

et al. 2019

Cardiovascular Research

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“…RTKs often function as entry points, integrating external inputs and driving intracellular responses. The RTKs include several important subfamilies of receptors such as FGFRs, EGFRs, VEGFRs, and PDGFRs, and are implicated in a broad range of cellular responses including embryonic development, angiogenesis, oncogenesis, and metabolism (McKay and Morrison, ; Li et al, ; Sewduth and Santoro, ).…”

Section: Receptor Tyrosine Kinasesmentioning

confidence: 99%

Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions

Menchero

Rayón

Andreu

et al. 2016

Developmental Dynamics

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The first stages of mammalian development, before implantation of the embryo in the maternal uterus, result in the establishment of three cell populations in the blastocyst: trophectoderm, epiblast, and primitive endoderm. These events involve only a small number of cells, and are initiated by morphological differences among them related to cell adhesion and polarity. Much attention has been paid to the master transcription factors that are critical for establishing and maintaining early lineage choices. Nevertheless, a large body of work also reveals that additional molecular mechanisms are involved. Here, we provide an updated view of the role of different signaling pathways in the first stages of mouse development, and how their cross-talk and interplay determine the initial lineage decisions occurring in the blastocyst. We will also discuss how these pathways are critical for translating cellular phenotypes, the product of the morphogenetic events occurring at these stages, into transcriptional responses and expression of lineage-specifying transcription factors. Developmental Dynamics 246:245-261, 2017. V C 2016 Wiley Periodicals, Inc.

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“…Recent studies highlighted intrahepatic angiogenesis as novel targets for the prevention and treatment of many diseases . Thus, a better understanding of the mechanism was effective to intervene in pathophysiological conditions . Recent researches also indicated that capillaries served as a direct source of supplying nutrients and oxygen to the fibrotic mass, and therefore angiogenesis played a critical role in fibrogenesis .…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis

et al. 2017

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Accumulating evidence indicates that hedgehog signaling plays a pivotal role in pathological angiogenesis and is involved in wound-healing responses in a number of adult tissues, including the liver. We previously demonstrated that hedgehog signaling promoted proliferation and inhibited apoptosis in hepatic stellate cells. This study was aimed to evaluate the effect of tetramethylpyrazine (TMP) on hedgehog signaling and to further examine the molecular mechanisms of TMP-induced antiangiogenesic effects in liver fibrosis. We found that TMP ameliorated the expression of proangiogenic markers vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor BB (PDGF-BB), platelet-derived growth factor-β receptor (PDGF-βR) and hypoxia inducible factor 1α (HIF-1α), concomitant with reduced abundance of endothelial markers platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), CD34 and von willebrand factor in vivo and in vitro. Interestingly, TMP attenuated the abundance of sonic hedgehog, smoothened (Smo) and glioblastoma but increased the expression of hedgehog-interacting protein in liver sinusoidal endothelial cells, which was underlying mechanism for the antiangiogenesic activity of TMP. Downregulation of Smo activity, using selective Smo inhibitor cyclopamine, lead to a synergistic effect with TMP, whereas Smo overexpression plasmid impaired the induction of antiangiogenesic effects of TMP. Overall, these results provide novel implications to reveal the molecular mechanism of TMP-inhibited liver sinusoidal angiogenesis, by which points to the possibility of using TMP-based antiangiogenic drugs for the treatment of liver fibrosis. © 2017 IUBMB Life, 69(2):115-127, 2017.

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“Decoding” Angiogenesis: New Facets Controlling Endothelial Cell Behavior

Cited by 35 publications

References 67 publications

Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions

Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis

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