Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor.
Vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) are members of a dimeric-growth-factor family with angiogenic properties. VEGF is a highly potent and specific mitogen for endothelial cells, playing a vital role in angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric splice forms VEGF-165, VEGF-121, PIGF-1 and PIGF-2 as unfused genes in Escherichia coli using the pCYTEXP expression system. In vitro dimerization experiments revealed that both homo- and hetero-dimers can be formed from these monomeric proteins. The dimers were tested for their ability to promote capillary growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial cells. Heterodimers comprising different VEGF splice forms, or combinations of VEGF/PIGF splice forms, showed mitogenic activity. The results demonstrate that four different heterodimeric growth factors are likely to have as yet uncharacterized functions in vivo.
Birkenhäger
R
R
Department of Gene Expression, National Biotechnology Research Centre (GBF), Braunschweig, Federal Republic of Germany.
Schneppe
B
B
Röckl
W
W
Wilting
J
J
Weich
H A
HA
McCarthy
J E
JE
D017398:Alternative Splicing; D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D003001:Cloning, Molecular; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004926:Escherichia coli; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010920:Placenta; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015183:Restriction Mapping; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor