Endothelial PFKFB3 plays a critical role in angiogenesis

Yiming Xu, Xiaofei An, Xin Guo, Tsadik Ghebreamlak Habtetsion, Yong Wang, Xizhen Xu, Sridhar Kandala, Qinkai Li, Honggui Li, Chunxiang Zhang, Ruth B Caldwell, David J Fulton, Yunchao Su, MD Nasrul Hoda, Gang Zhou, Chaodong Wu, Yuqing Huo

Research output: Contribution to journalArticle

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Abstract

Objective-Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2- kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Approach and Results-Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. Conclusions-The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.

Original languageEnglish (US)
Pages (from-to)1231-1239
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number6
DOIs
StatePublished - Jan 1 2014

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Phosphofructokinase-2
Protein Isoforms
Glycolysis
Endothelial Cells
Lactic Acid
Pathologic Neovascularization
Proto-Oncogene Proteins c-akt
Angiogenesis Inducing Agents
Blood Vessels
Retina

Keywords

  • angiogenesis
  • anoxia
  • endothelial cells
  • glycolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Endothelial PFKFB3 plays a critical role in angiogenesis. / Xu, Yiming; An, Xiaofei; Guo, Xin; Habtetsion, Tsadik Ghebreamlak; Wang, Yong; Xu, Xizhen; Kandala, Sridhar; Li, Qinkai; Li, Honggui; Zhang, Chunxiang; Caldwell, Ruth B; Fulton, David J; Su, Yunchao; Hoda, MD Nasrul; Zhou, Gang; Wu, Chaodong; Huo, Yuqing.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 34, No. 6, 01.01.2014, p. 1231-1239.

Research output: Contribution to journalArticle

Xu, Y, An, X, Guo, X, Habtetsion, TG, Wang, Y, Xu, X, Kandala, S, Li, Q, Li, H, Zhang, C, Caldwell, RB, Fulton, DJ, Su, Y, Hoda, MDN, Zhou, G, Wu, C & Huo, Y 2014, 'Endothelial PFKFB3 plays a critical role in angiogenesis', Arteriosclerosis, thrombosis, and vascular biology, vol. 34, no. 6, pp. 1231-1239. https://doi.org/10.1161/ATVBAHA.113.303041
Xu, Yiming ; An, Xiaofei ; Guo, Xin ; Habtetsion, Tsadik Ghebreamlak ; Wang, Yong ; Xu, Xizhen ; Kandala, Sridhar ; Li, Qinkai ; Li, Honggui ; Zhang, Chunxiang ; Caldwell, Ruth B ; Fulton, David J ; Su, Yunchao ; Hoda, MD Nasrul ; Zhou, Gang ; Wu, Chaodong ; Huo, Yuqing. / Endothelial PFKFB3 plays a critical role in angiogenesis. In: Arteriosclerosis, thrombosis, and vascular biology. 2014 ; Vol. 34, No. 6. pp. 1231-1239.
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abstract = "Objective-Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2- kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Approach and Results-Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. Conclusions-The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.",
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T1 - Endothelial PFKFB3 plays a critical role in angiogenesis

AU - Xu, Yiming

AU - An, Xiaofei

AU - Guo, Xin

AU - Habtetsion, Tsadik Ghebreamlak

AU - Wang, Yong

AU - Xu, Xizhen

AU - Kandala, Sridhar

AU - Li, Qinkai

AU - Li, Honggui

AU - Zhang, Chunxiang

AU - Caldwell, Ruth B

AU - Fulton, David J

AU - Su, Yunchao

AU - Hoda, MD Nasrul

AU - Zhou, Gang

AU - Wu, Chaodong

AU - Huo, Yuqing

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Objective-Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2- kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Approach and Results-Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. Conclusions-The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.

AB - Objective-Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2- kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Approach and Results-Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. Conclusions-The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.

KW - angiogenesis

KW - anoxia

KW - endothelial cells

KW - glycolysis

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