Temporally expressed PDGF and FGF-2 regulate embryonic coronary artery formation and growth.
OBJECTIVE
PDGF and FGF-2 are important regulators of vascular wall assembly. We tested the hypothesis that their embryonic temporal expression facilitates 2 specific events: (1) the endothelial invasion of the aortic root to form the coronary artery stems and (2) the subsequent growth and development of the arterial tree.


RESULTS
Addition of FGF-2 and PDGF-BB proteins to embryonic quail heart explants stimulated a 3- and 7-fold increase, respectively, in tubulogenesis, whereas neutralizing antibodies to these growth factors attenuated tubulogenesis by 40%. Anti-FGF-2 and anti-PDGF neutralizing antibodies were then introduced in ovo via the vitelline vein at various embryonic (E) days. When injections occurred before coronary ostial formation, the embryos usually developed only 1 coronary artery or lacked coronary arteries. When 1 or both major coronary arteries formed: (1) their branches had a thinner tunica media, and (2) smooth muscle investment did not progress as far distally as in shams. Other anomalies included smaller diameter coronary artery stems in some hearts. Inhibition of VEGF via injections of aflibercept (VEGF-Trap, a VEGFR-1 and -2 chimera), previously shown to be essential for coronary stem formation, limited development of the coronary arteries even though introduced after formation of coronary ostia (at E9 or EI0).


CONCLUSIONS
Our data (1) document a role for FGF-2 and PDGF in the temporal regulation of coronary artery stem formation and growth of the coronary arterial tree and (2) reveal that VEGF expression is required for normal artery/arterial formation, even after coronary artery stem formation.
Tomanek
Robert J
RJ
Department of Anatomy & Cell Biology, The University of Iowa, 1-402 Bowen Science Building, Iowa City, Iowa 52242, USA. robert-tomanek@uiowa.edu
Hansen
Heidi K
HK
Christensen
Lance P
LP
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D000077214:Becaplermin; D003331:Coronary Vessels / Q000187:drug effects / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D011784:Quail; D011994:Recombinant Proteins / Q000378:metabolism; D012107:Research Design; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin