Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways

Seon Jin Lee, Seung Namkoong, Young Mi Kim, Chun Ki Kim, Hansoo Lee, Kwon Soo Ha, Hun Taeg Chung, Young Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Fractalkine (FKN) has been implicated in modulation of angiogenesis and vascular inflammation, but the underlying mechanism has not been elucidated. We have investigated the molecular mechanism by which FKN regulates angiogenesis. We found that recombinant FKN increases in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells and stimulates in vivo angiogenesis. FKN-induced angiogenesis was accompanied by phosphorylation of ERK, Akt, and endothelial nitric oxide (NO) synthase (eNOS), as well as an increase in NO production. These biochemical events and angiogenesis were completely inhibited by the G protein-coupled receptor inhibitor pertussis toxin. Inhibitors of Raf-1, MEK, phosphatidylinositol 3-kinase (PI3K), and eNOS or transfection with dominant-negative forms of ERK and Akt significantly suppressed the angiogenic activity of FKN. However, inhibitors of Raf-1 and MEK or a dominant-negative ERK mutant blocked FKN-induced ERK, but not Akt and eNOS, phosphorylation. The PI3K inhibitor and a dominant-negative mutant of Akt suppressed Akt and eNOS phosphorylation and NO production. Our results demonstrated that FKN stimulated angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1, indicating that two pathways are required for full angiogenic activity of FKN. This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis.

Original languageEnglish
Pages (from-to)H2836-H2846
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number6
DOIs
Publication statusPublished - 2006 Dec 18

Fingerprint

Chemokine CX3CL1
Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinase Kinases
Signal Transduction
Nitric Oxide
Phosphorylation
G-Protein-Coupled Receptors
Nitric Oxide Synthase Type III
Pertussis Toxin
Human Umbilical Vein Endothelial Cells
Transfection
Blood Vessels
Inflammation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lee, Seon Jin ; Namkoong, Seung ; Kim, Young Mi ; Kim, Chun Ki ; Lee, Hansoo ; Ha, Kwon Soo ; Chung, Hun Taeg ; Kwon, Young Guen ; Kim, Young Myeong. / Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways. In: American Journal of Physiology - Heart and Circulatory Physiology. 2006 ; Vol. 291, No. 6. pp. H2836-H2846.
@article{04bf7dc74c734aa9be17f24588313125,
title = "Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways",
abstract = "Fractalkine (FKN) has been implicated in modulation of angiogenesis and vascular inflammation, but the underlying mechanism has not been elucidated. We have investigated the molecular mechanism by which FKN regulates angiogenesis. We found that recombinant FKN increases in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells and stimulates in vivo angiogenesis. FKN-induced angiogenesis was accompanied by phosphorylation of ERK, Akt, and endothelial nitric oxide (NO) synthase (eNOS), as well as an increase in NO production. These biochemical events and angiogenesis were completely inhibited by the G protein-coupled receptor inhibitor pertussis toxin. Inhibitors of Raf-1, MEK, phosphatidylinositol 3-kinase (PI3K), and eNOS or transfection with dominant-negative forms of ERK and Akt significantly suppressed the angiogenic activity of FKN. However, inhibitors of Raf-1 and MEK or a dominant-negative ERK mutant blocked FKN-induced ERK, but not Akt and eNOS, phosphorylation. The PI3K inhibitor and a dominant-negative mutant of Akt suppressed Akt and eNOS phosphorylation and NO production. Our results demonstrated that FKN stimulated angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1, indicating that two pathways are required for full angiogenic activity of FKN. This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis.",
author = "Lee, {Seon Jin} and Seung Namkoong and Kim, {Young Mi} and Kim, {Chun Ki} and Hansoo Lee and Ha, {Kwon Soo} and Chung, {Hun Taeg} and Kwon, {Young Guen} and Kim, {Young Myeong}",
year = "2006",
month = "12",
day = "18",
doi = "10.1152/ajpheart.00113.2006",
language = "English",
volume = "291",
pages = "H2836--H2846",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6",

}

Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways. / Lee, Seon Jin; Namkoong, Seung; Kim, Young Mi; Kim, Chun Ki; Lee, Hansoo; Ha, Kwon Soo; Chung, Hun Taeg; Kwon, Young Guen; Kim, Young Myeong.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 291, No. 6, 18.12.2006, p. H2836-H2846.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways

AU - Lee, Seon Jin

AU - Namkoong, Seung

AU - Kim, Young Mi

AU - Kim, Chun Ki

AU - Lee, Hansoo

AU - Ha, Kwon Soo

AU - Chung, Hun Taeg

AU - Kwon, Young Guen

AU - Kim, Young Myeong

PY - 2006/12/18

Y1 - 2006/12/18

N2 - Fractalkine (FKN) has been implicated in modulation of angiogenesis and vascular inflammation, but the underlying mechanism has not been elucidated. We have investigated the molecular mechanism by which FKN regulates angiogenesis. We found that recombinant FKN increases in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells and stimulates in vivo angiogenesis. FKN-induced angiogenesis was accompanied by phosphorylation of ERK, Akt, and endothelial nitric oxide (NO) synthase (eNOS), as well as an increase in NO production. These biochemical events and angiogenesis were completely inhibited by the G protein-coupled receptor inhibitor pertussis toxin. Inhibitors of Raf-1, MEK, phosphatidylinositol 3-kinase (PI3K), and eNOS or transfection with dominant-negative forms of ERK and Akt significantly suppressed the angiogenic activity of FKN. However, inhibitors of Raf-1 and MEK or a dominant-negative ERK mutant blocked FKN-induced ERK, but not Akt and eNOS, phosphorylation. The PI3K inhibitor and a dominant-negative mutant of Akt suppressed Akt and eNOS phosphorylation and NO production. Our results demonstrated that FKN stimulated angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1, indicating that two pathways are required for full angiogenic activity of FKN. This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis.

AB - Fractalkine (FKN) has been implicated in modulation of angiogenesis and vascular inflammation, but the underlying mechanism has not been elucidated. We have investigated the molecular mechanism by which FKN regulates angiogenesis. We found that recombinant FKN increases in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells and stimulates in vivo angiogenesis. FKN-induced angiogenesis was accompanied by phosphorylation of ERK, Akt, and endothelial nitric oxide (NO) synthase (eNOS), as well as an increase in NO production. These biochemical events and angiogenesis were completely inhibited by the G protein-coupled receptor inhibitor pertussis toxin. Inhibitors of Raf-1, MEK, phosphatidylinositol 3-kinase (PI3K), and eNOS or transfection with dominant-negative forms of ERK and Akt significantly suppressed the angiogenic activity of FKN. However, inhibitors of Raf-1 and MEK or a dominant-negative ERK mutant blocked FKN-induced ERK, but not Akt and eNOS, phosphorylation. The PI3K inhibitor and a dominant-negative mutant of Akt suppressed Akt and eNOS phosphorylation and NO production. Our results demonstrated that FKN stimulated angiogenesis by activating the Raf-1/MEK/ERK and PI3K/Akt/eNOS/NO signal pathways via the G protein-coupled receptor CX3CR1, indicating that two pathways are required for full angiogenic activity of FKN. This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis.

UR - http://www.scopus.com/inward/record.url?scp=33845467811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845467811&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00113.2006

DO - 10.1152/ajpheart.00113.2006

M3 - Article

C2 - 16877565

AN - SCOPUS:33845467811

VL - 291

SP - H2836-H2846

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6

ER -