Abstract 790: Hedgehog Signaling Represents a Novel Therapeutic Target for Coronary Neo-Angiogenesis and Is Essential for Embryonic Coronary Development and Maintenance of the Coronary Vasculature in the Adult
Myocardial infarction and ischemic heart disease are the leading causes of death in the industrial world. Therapies employed for treating these diseases are aimed at promoting increased blood flow to cardiac tissue. In addition to current surgical and interventional approaches, pharmacological induction of new coronary growth has recently been explored, however, clinical trials with known pro-angiogenic factors have been disappointing. To identify novel therapeutic targets we have examined signaling pathways that govern the formation of the coronary vascular system during embryonic development. Using a combination of genetically engineered mice and an organ culture system we identified a novel signaling pathway mediated by Fibroblast Growth Factor (FGF) and Hedgehog (HH) signaling that is essential for the development of the coronary vasculature. We show that FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast through redundant function of FGF receptors 1 and 2. Myocardial FGF signaling triggers a wave of HH activation that is essential for Vegf-A, Vegf-B, Vegf-C and Ang2 expression. We further demonstrate that activation of HH signaling is sufficient to promote coronary vessel growth and to rescue coronary defects due to loss of FGF signaling. Moreover, disruption of HH signaling results in failure of coronary artery and vein development and loss of pro-angiogenic factor expression. These studies implicate HH signaling as a master regulator of coronary vascular development and as a potential therapeutic target for coronary neo-angiogenesis. Consistent with this, activation of HH signaling in the adult heart leads to coordinated growth of multiple coronary vessel types and protects from myocardial ischemia. Moreover, we demonstrate that HH signaling is essential for the maintenance of the coronary vasculature under physiologic conditions and is critical for the response to cardiac ischemia.