The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis

被引：127

作者：

Cudmore, Melissa J. ^{[1
]}

Hewett, Peter W. ^{[2
]}

Ahmad, Shakil ^{[1
]}

Wang, Ke-Qing ^{[1
]}

Cai, Meng ^{[1
]}

Al-Ani, Bahjat ^{[3
]}

Fujisawa, Takeshi ^{[1
]}

Ma, Bin ^{[1
]}

Sissaoui, Samir ^{[2
]}

Ramma, Wenda ^{[1
]}

Miller, Mark R. ^{[1
]}

Newby, David E. ^{[1
]}

Gu, Yuchun ^{[4
]}

Barleon, Bernhard ^{[5
]}

Weich, Herbert ^{[6
]}

Ahmed, Asif ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Coll Med & Vet Med, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh EH16 4TJ, Midlothian, Scotland

[2] Univ Birmingham, Coll Med & Dent Sci, Inst Biomed Res, Dept Reprod & Vasc Biol, Birmingham B15 2TT, W Midlands, England

[3] King Khalid Univ, Coll Med, Dept Physiol, Abha 62529, Saudi Arabia

[4] Peking Univ, IMM, Beijing 100871, Peoples R China

[5] RELIATech, D-38124 Braunschweig, Germany

[6] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

基金：

英国医学研究理事会;

关键词：

GROWTH-FACTOR RECEPTOR-1; NITRIC-OXIDE SYNTHASE; SIGNAL-TRANSDUCTION; MEDIATED ANGIOGENESIS; TYROSINE KINASE; ANGIOTENSIN-II; GENE DELIVERY; CROSS-TALK; ORF-VIRUS; IN-VITRO;

D O I：

10.1038/ncomms1977

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.

引用

页数：12

共 60 条

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