Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice
Kory J. Lavine, … , Attila Kovacs, David M. Ornitz
Kory J. Lavine, … , Attila Kovacs, David M. Ornitz
Published June 20, 2008
Citation Information: J Clin Invest. 2008;118(7):2404-2414. https://doi.org/10.1172/JCI34561.
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Research Article Vascular biology

Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice

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.

Authors

Kory J. Lavine, Attila Kovacs, David M. Ornitz

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Figure 7

Endogenous HH signaling is critical for recovery following cardiac ischemia.

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Endogenous HH signaling is critical for recovery following cardiac ische...
(A) Kaplan-Meier survival curve showing the initial lethality following LAD ligation in both control and SHH Ab groups. However, between days 4 and 7 after MI, a fraction of the mice receiving SHH Ab died. The red arrow denotes the time at which mice underwent LAD ligation, and the red bar indicates the days mice received Ab injections. (B and C) Long-axis end-systolic images of control (B) and SHH Ab–treated (C) hearts, demonstrating diminished ventricular function in SHH Ab–treated mice. Green arrows highlight the LV cavity. (D and E) Pairwise comparison of ejection fraction 1 day after MI (prior to Ab injections) and 14 days after MI (after Ab injections) in control (D) and SHH Ab–treated (E) mice. (F) Quantitation of the relative change in ejection fraction, demonstrating that SHH Ab–treated mice undergo a more severe decline in cardiac function compared with control mice (*P < 0.01). (G–J) Trichrome staining (G and H) and short-axis echocardiographic images (I and J) of control (G and I) and SHH Ab–treated (H and J) mice showing increased infarct size in SHH Ab–treated animals. Green arrows denote the infarct border zones. Original magnification, ×25 (G and H). (K and L) Pairwise comparison of infarct area 1 day after MI (prior to Ab injections) and 14 days after MI (after Ab injections) in control (K) and SHH Ab–treated (L) mice. (M) Quantitation of the relative change in infarct area (IA), demonstrating that SHH Ab–treated mice undergo an exaggerated increase in infarct area compared with control mice (*P < 0.01).