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. 2023 Mar 2;13(1):43.
doi: 10.1186/s13578-023-00980-1.

Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves

Dongsheng Gu #  1 , Arvin H Soepriatna #  2   3 , Wenjun Zhang  1 , Jun Li  4 , Jenny Zhao  1   5 , Xiaoli Zhang  1 , Xianhong Shu  4 , Yongshi Wang  6 , Benjamin J Landis  7 , Craig J Goergen  8 , Jingwu Xie  9   10
Affiliations

Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves

Dongsheng Gu et al. Cell Biosci. .

Abstract

Background: Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models.

Results: In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves.

Conclusions: Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.

Keywords: Aortic valve; Fibrosis; Hedgehog; Smoothened; Stenosis.

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Conflict of interest statement

The authors declare that they have no competing interest.

Figures

Fig. 1
Fig. 1
Physical features of FSP1-cre + /SmoM2 + mice. A shows a diagram for mouse mating. B shows Kaplan meier survival curves from the control and FSP1-cre + /SmoM2 + mice (p = 0.0005). Mice with SmoM2 expression exhibit progressive weight loss (C), ear swelling (D), and coarse fur (E) compared to control mice
Fig. 2
Fig. 2
Fibrotic phenotypes in FSP1-cre/SmoM2 mice. A shows detection of fibrosis by Sirius Red staining (shown in red) in vasculature of lung, while B shows fibrosis (shown in red) in heart vasculature. The relative level of vasculature fibrosis was indicated by the percentage of Sirius Red positive area in the total blool vessel area, and the average from 10 blood vessels was shown at the right of each figure. * indicates p < 0.05
Fig. 3
Fig. 3
Aortic valve fibrosis in FSP1-cre+/SmoM2.+ mice. A shows pentachrome staining of fibrotic tissue (yellow suggestive of collagen diposition). Please note collagen deposition and size of the aortic valve hinge region and annulus. * shows the site with potential calcification. B shows the average of the aortic valve root thickness from 8 mice. # indicates significant difference (p < 0.05) between FSP1-cre + Smo- (or wild-type) mice and FSP1-cre + Smo + mice. C shows gene expression levels of hedgehog target genes Gli1, Hip1, and other genes (Pai1 and Spp1) known to be involved in fibrosis. # indicates significant changes in comparison with aortic valves from control mice (p < 0.05). The control value is set as 1
Fig. 4
Fig. 4
Echocardiographic analyses of aortic valve and heart function. Representative M-mode and PW Doppler images of the aortic valve (top) and transmitral flow (bottom) in both (A) WT-control and (B) FSP1+/SmoM2+ mice are shown. Significant systolic dysfunction is observed in FSP1+/SmoM2+ mice, as shown by a progressive decline in (C) stroke volume, D ejection fraction, and E cardiac output starting at week 8. F Aortic cusp separation, normalized to aortic root diameter, progressively decreased starting week 8 in FSP1+/SmoM2+, suggesting a stiffer aortic valve. G An increase in aortic valve outflow velocity, relative to inflow velocity, is consistent with aortic stenosis. H FSP1+/SmoM2+ mice exhibited E/A ratio inversion, suggesting impaired diastolic relaxation of the left ventricle
Fig. 5
Fig. 5
Analyses of normal and diseased aortic valve leaflets. A shows the width of aortic valves; B shows gene expression in human aortic valves, specimen# 12 and #13 were normal aortic valves. * indicates significant changes (in comparison with normal valves) (p < 0.05)
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References

    1. Sasaki H, Hui C, Nakafuku M, Kondoh H. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development. 1997;124:1313–1322. doi: 10.1242/dev.124.7.1313. - DOI - PubMed
    1. Kinzler KW, Vogelstein B. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol. 1990;10:634–642. - PMC - PubMed
    1. Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet. 2006;7:841–850. doi: 10.1038/nrg1969. - DOI - PubMed
    1. Hu L, Lin X, Lu H, Chen B, Bai Y. An overview of hedgehog signaling in fibrosis. Mol Pharmacol. 2015;87:174–182. doi: 10.1124/mol.114.095141. - DOI - PubMed
    1. Kramann R. Hedgehog Gli signalling in kidney fibrosis. Nephrol Dial Transplant. 2016;31:1989–1995. doi: 10.1093/ndt/gfw102. - DOI - PubMed

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