Abstract
Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of HH signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure, and subsequent lethality. We further showed that HH signaling specifically controlled the survival of small coronary arteries and capillaries. Together, these data demonstrate that HH signaling is essential for cardiac function at the level of the coronary vasculature and caution against the use of HH antagonists in patients with prior or ongoing heart disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenic Proteins / genetics
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology
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Cardiomegaly / genetics
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Cardiomegaly / pathology
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Coronary Vessels / metabolism
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Coronary Vessels / pathology
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Coronary Vessels / physiopathology*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibrosis
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Heart / drug effects
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Heart / physiopathology
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Hedgehog Proteins / genetics
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Hedgehog Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism
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Myocardial Ischemia / metabolism
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Myocardial Ischemia / pathology
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Myocardial Ischemia / physiopathology
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Myocardium / metabolism
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Myocardium / pathology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Patched Receptors
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Receptors, Cell Surface / metabolism
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Receptors, G-Protein-Coupled / deficiency
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Receptors, G-Protein-Coupled / genetics
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Smoothened Receptor
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Veratrum Alkaloids / pharmacology
Substances
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Angiogenic Proteins
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Hedgehog Proteins
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Patched Receptors
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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Shh protein, mouse
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Smo protein, mouse
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Smoothened Receptor
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Veratrum Alkaloids
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cyclopamine