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 1

SHH and PTC1 expression in the adult heart.

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SHH and PTC1 expression in the adult heart. (A–D) Immunohistochemical st...
(A–D) Immunohistochemical staining of Ptc1-LacZ adult hearts with Abs against cardiac actin (B, green) and β-galactosidase (C, red) demonstrating PTC1 expression in cardiomyocytes (white arrows) and large coronary vessels (white arrowheads). A shows the corresponding differential interference contrast (DIC) microscopy image. (E–H) Immunohistochemical staining of Ptc1-LacZ adult hearts with Abs against PECAM (E, blue), SMA (F, green), and β-galactosidase (G, red). PTC1 expression was detected in both cardiomyocytes and perivascular smooth muscle cells. White arrowheads denote colocalization of PTC1 and SMA expression. (I–L) Immunohistochemical staining with Abs against PECAM (I, blue), vimentin (J, green), and SHH (K, red) revealed that SHH is expressed in adventitial and interstitial fibroblasts. White arrowheads denote colocalization of SHH and vimentin expression. The asterisk indicates area of vimentin and PECAM coexpression. (M–P) Immunostaining with PECAM (M, blue), SHH (N, green), and β-galactosidase (O, red) demonstrates a close association among SHH-expressing interstitial fibroblasts, PTC1-expressing cardiomyocytes, and blood vessels (white arrowhead). In E–G, I–K, and M–O, florescent signals are overlaid on top of DIC images. D, H, L, and P show merged images of A–C, E–G, I–K, and M–O, respectively. Original magnification, ×400 (A–D, I–L, and M–P); ×200 (E–H).