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Recapitulation of developmental mechanisms to revascularize the ischemic heart
Karina N. Dubé, … , Paul R. Riley, Nicola Smart
Karina N. Dubé, … , Paul R. Riley, Nicola Smart
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e96800. https://doi.org/10.1172/jci.insight.96800.
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Research Article Cardiology

Recapitulation of developmental mechanisms to revascularize the ischemic heart

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Abstract

Restoring blood flow after myocardial infarction (MI) is essential for survival of existing and newly regenerated tissue. Endogenous vascular repair processes are deployed following injury but are poorly understood. We sought to determine whether developmental mechanisms of coronary vessel formation are intrinsically reactivated in the adult mouse after MI. Using pulse-chase genetic lineage tracing, we establish that de novo vessel formation constitutes a substantial component of the neovascular response, with apparent cellular contributions from the endocardium and coronary sinus. The adult heart reverts to its former hypertrabeculated state and repeats the process of compaction, which may facilitate endocardium-derived neovascularization. The capacity for angiogenic sprouting of the coronary sinus vein, the adult derivative of the sinus venosus, may also reflect its embryonic origin. The quiescent epicardium is reactivated and, while direct cellular contribution to new vessels is minimal, it supports the directional expansion of the neovessel network toward the infarcted myocardium. Thymosin β4, a peptide with roles in vascular development, was required for endocardial compaction, epicardial vessel expansion, and smooth muscle cell recruitment. Insight into pathways that regulate endogenous vascular repair, drawing on comparisons with development, may reveal novel targets for therapeutically enhancing neovascularization.

Authors

Karina N. Dubé, Tonia M. Thomas, Sonali Munshaw, Mala Rohling, Paul R. Riley, Nicola Smart

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Figure 7

Growth of a vascular network after myocardial infarction within the reactivated epicardium.

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Growth of a vascular network after myocardial infarction within the reac...
Shown by immunostaining, the single-cell layer epicardium of the noninjured mouse heart (A) expands rapidly in response to injury, from day 2 after MI (B), continuing to day 14 (C–F). A network of capillaries arises within the activated epicardium between day 4 and day 7 (PECAM1+ endothelial cells in green; αSMA+ vascular smooth muscle cells in red (C–E). Epicardial capillaries remodel to form arterioles (F and G), acquiring smooth muscle support (D–H) and connecting with the underlying coronary vasculature (arrowhead in G). Maximal epicardial activity was observed in the proximity of the infarct (H), with only modest thickening over remote regions of the LV (I). Representative of 24 hours: n = 5 (2 sham); 2 days: n = 6 (3 sham); 4 days: n = 5 (2 sham); 7 days: n = 15 (4 sham); 14 days: n = 5 (2 sham). qRT-PCR confirmed the reexpression of fetal epicardial genes, Wt1, Tbx18, Tcf21, and Aldh1a2 (J, fold change relative to day 2 MI; n = 4 separate animals per time point; mean ± SEM; 2-tailed Kruskal-Wallis nonparametric test with Dunn’s post-hoc test for multiple comparisons; *P ≤ 0.05, ***P ≤ 0.001). WT-1 reactivation in the epicardium, comparing sham (K) and day 2 after MI (L) hearts by immunostaining (boxes in K and L correspond to enlarged insets). PdgfbCreERT2; R26R-EYFP pulse-labeling experiments (M; box enlarged in N and O) indicate that 30.1% ± 3.8% of endothelial cells within the expanded epicardium derived from nonendothelial progenitors or endocardium (arrows in N and O indicate EYFP+ cells; arrowheads indicate EYFP– cells; quantified in P). LV, left ventricle; epi, epicardium; myo, myocardium. Scale bars: 50 μm (A–E, G, and M); 100 μm (H, K, and L); 200 μm (F and I); 20 μm (N and O).

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