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

¹ Department of Molecular Biology and Pharmacology, ² Department of Pathology and Immunology ³ Department of Internal Medicine, Washington University Medical School, St. Louis, Missouri 63110, USA; ⁴ Program in Developmental Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X8 Canada

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.

[Keywords: Fibroblast growth factor (FGF); Hedgehog (HH); heart development; coronary vascular development; coronary neoangiogenesis]

Received January 20, 2006; revised version accepted April 12, 2006.

E-MAIL dornitz{at}wustl.edu; FAX (314) 362-7058.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1411406

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