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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1237.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Temporally Expressed PDGF and FGF-2 Regulate Embryonic Coronary Artery Formation and Growth

Robert J. Tomanek; Heidi K. Hansen; Lance P. Christensen

From the Department of Anatomy and Cell Biology, and The Cardiovascular Center, Carver College of Medicine, Iowa City, Iowa.

Correspondence to Robert J. Tomanek, PhD, Department of Anatomy & Cell Biology, The University of Iowa, 1-402 Bowen Science Building, Iowa City, Iowa 52242. E-mail robert-tomanek{at}uiowa.edu

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.

Methods and 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.

Key Words: arteriogenesis • angiogenesis • VEGF • FGF-2 • PDGF • coronary arteries