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1: Genes Dev. 2006 Jun 15;20(12):1651-66.

Fibroblast growth factor signals regulate a wave of Hedgehog activation that is
essential for coronary vascular development.

Lavine KJ, White AC, Park C, Smith CS, Choi K, Long F, Hui CC, Ornitz DM.

Department of Molecular Biology and Pharmacology, Washington University Medical
School, St. Louis, Missouri 63110, USA.

Myocardial infarction and ischemic heart disease are the leading cause of death
in the industrial world. Therapies employed for treating these diseases are aimed
at promoting increased blood flow to cardiac tissue. Pharmacological induction of
new coronary growth has recently been explored, however, clinical trials with
known proangiogenic factors have been disappointing. To identify novel
therapeutic targets, we have explored signaling pathways that govern embryonic
coronary development. Using a combination of genetically engineered mice and an
organ culture system, we identified novel roles for fibroblast growth factor
(FGF) and Hedgehog (HH) signaling in coronary vascular development. We show that 
FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast
through redundant function of Fgfr1 and Fgfr2. Myocardial FGF signaling triggers 
a wave of HH activation that is essential for vascular endothelial growth factor 
(Vegf)-A, Vegf-B, Vegf-C, and angiopoietin-2 (Ang2) expression. We demonstrate
that HH is necessary for coronary vascular development and activation of HH
signaling is sufficient to promote coronary growth and to rescue coronary defects
due to loss of FGF signaling. These studies implicate HH signaling as an
essential regulator of coronary vascular development and as a potential
therapeutic target for coronary neovascularization. Consistent with this,
activation of HH signaling in the adult heart leads to an increase in coronary
vessel density.

PMID: 16778080 [PubMed - indexed for MEDLINE]

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