Control of vessel sprouting by genetic and metabolic determinants

Eelen, Guy; Cruys, Bert; Welti, Jonathan; Bock, Katrien De; Carmeliet, Peter

doi:10.1016/j.tem.2013.08.006

Cited by 60 publications

(57 citation statements)

References 64 publications

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“…ECs tend to form tip cell phenotype to bud blood vessels under a high lactic acid concentration. At the same time, another part of ECs translate into a stalk cell phenotype, obtaining strong proliferation ability leading to new sprout growth into vessel branches (18).…”

Section: Discussionmentioning

confidence: 99%

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Wang

Liu

et al. 2016

Oncology Reports

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Abstract. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) and monocarboxylate transporter 1 (MCT1) play important roles in tumor endothelial cells (ECs) and several biological processes. The present study was conducted to study the effects of PFKFB3 and MCT1 on cell proliferation and apoptosis in the tumor microenvironment by co-culture of HUVECs and T24, a bladder cancer (BC) cell line, using a microfluidic device. Immunofluorescence assay showed that HUVEC activity was significantly enhanced under co-culture with T24 cells, according to the stronger fluorescence intensity of CD31 and CD105 than that in the signal-cultured cells. Quercetin treatment inhibited MCT1 expression but did not affect PFKFB3 expression. Knockdown of MCT1 or/and PFKFB3 increased the apoptosis rate of the HUVECs under single-culture and co-culture situations by staining with calcein and propidium iodide. Meanwhile, cell proliferation and lactic concentration were significantly decreased after the blocking of MCT1 or/and PFKFB3, as compared with that in the control group. No obvious differences in the effects on apoptosis, proliferation and lactic concentration were found between cells treated with quercetin and siMCT1. Thus, we concluded that the targeting of MCT1 and PFKFB3 regulated cell proliferation and apoptosis in BC cells by altering the tumor microenvironment, and quercetin exhibited a potential antitumor effect by targeting MCT1.

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Section: Discussionmentioning

confidence: 99%

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Wang

Liu

et al. 2016

Oncology Reports

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“…The F2,6BP, an allosteric activator of phosphofructokinase‐1 (PFK‐1) and a potent stimulator of glycolysis, is synthesized and degraded by the enzymes named 6‐phosphofructo‐ 2‐kinase/fructose 2,6‐bisphosphatases (PFKFB1/2/3/4) . Notably, PFKFB3 is the most studied isoform among its isomerases due to its ubiquitous expression in human tissues and its high kinase/phosphatase activity ratio . Indeed, the ectopic expression of PFKFB3 has been shown to influence the physiological and pathological activity in various tissues.…”

Section: Introductionmentioning

confidence: 99%

PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage

Guo

et al. 2016

Clin Exp Pharma Physio

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Glycolytic disorder has been demonstrated to be a major cause of osteoarthritis (OA) and chondrocyte dysfunction. The present work aimed to investigate the expression and role of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in OA cartilage. It was found that PFKFB3 expression was down-regulated in human OA cartilage tissues and in tumour necrosis factor (TNF)-α- or interleukin (IL)-1β-stimulated human chondrocytes. The glycolytic metabolism appeared as glucose utilization and adenosine triphosphate (ATP) generation, and lactate production was stunted in OA cartilage. However, the impaired glycolytic process in OA cartilage was improved by PFKFB3 overexpression, which was confirmed in TNF-α- or IL-1β-treated chondrocytes. Furthermore, the expressions of endoplasmic reticulum (ER) stress-associated genes including PERK, ATF3, IRE1, phosphorylated eIF2α (p-eIF2α) and MMP13 were enhanced in OA cartilage explants, while they were decreased by AdPFKFB3 transfection. PFKFB3 also modulated the expressions of PERK, ATF3, IRE1, p-eIF2α and MMP13 in tunicamycin-exposed chondrocytes. Additionally, PFKFB3 improved the cell viability of OA cartilage explants and chondrocytes through the PI3K/Akt/C/EBP homologous protein (CHOP) signalling pathway. The transfection of AdPFKFB3 also significantly reduced caspase 3 activation and promoted aggrecan and type II collagen expressions in OA cartilage explants and chondrocytes. In all, this study characterizes a novel role of PFKFB3 in glycolytic metabolism and ER stress of OA cartilage explants and chondrocytes. The study might provide a potential target for OA prevention or therapy.

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“…Despite a reliance on glycolysis, ECs contain functional mitochondria that are active during angiogenesis 2 . Endothelial mitochondria are therefore considered signaling organelles that modulate the angiogenic process 3 or supply biosynthetic molecules required for growth 4 . Precisely how mitochondrial metabolism impacts endothelial function and angiogenesis is virtually unknown.…”

Section: Introductionmentioning

confidence: 99%

The Mitochondrial Permeability Transition Pore Regulates Endothelial Bioenergetics and Angiogenesis

Marcu

Kotha

Zhi

et al. 2015

Circulation Research

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Rationale The mitochondrial permeability transition pore (mPTP) is a well-known initiator of cell death that is increasingly recognized as a physiological modulator of cellular metabolism. Objective We sought to identify how the genetic deletion of a key regulatory subunit of the mPTP, Cyclophilin D (CypD), influenced endothelial metabolism and intracellular signaling. Methods and Results In cultured primary human endothelial cells (ECs), genetic targeting of CypD using siRNA or shRNA resulted in a constitutive increase in mitochondrial matrix Ca2+ and NADH. Elevated matrix NADH in turn diminished the cytosolic NAD+/NADH ratio and triggered a subsequent downregulation of the NAD+-dependent deacetylase SIRT1. Downstream of SIRT1, CypD-deficient ECs exhibited reduced PTEN expression and a constitutive rise in the phosphorylation of angiogenic Akt. Similar changes in SIRT1, PTEN, and Akt were also noted in the aorta and lungs of CypD KO mice. Functionally, CypD-deficient ECs and aortic tissue from CypD KO mice exhibited a dramatic increase in angiogenesis at baseline and when exposed to vascular endothelial growth factor (VEGF). The NAD+ precursor Nicotinamide mononucleotide restored the cellular NAD+/NADH ratio and normalized the CypD-deficient phenotype. CypD KO mice also presented accelerated wound healing and increased neovascularization upon tissue injury as monitored by optical microangiography (OMAG). Conclusion Our study reveals the importance of the mPTP in the regulation of endothelial mitochondrial metabolism and vascular function. The mitochondrial regulation of SIRT1 has broad implications in the epigenetic regulation of endothelial phenotype.

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Control of vessel sprouting by genetic and metabolic determinants

Cited by 60 publications

References 64 publications

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage

The Mitochondrial Permeability Transition Pore Regulates Endothelial Bioenergetics and Angiogenesis

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