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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 5

Marker profiling supports an endocardial origin of de novo subendocardial vessels.

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Marker profiling supports an endocardial origin of de novo subendocardia...
By immunostaining, VEGFR2 was expressed in capillaries (A) and veins weakly (B and C) but not arteries (arrowhead, B) or endocardium (A and D). Subendocardial vessels, formed after myocardial infarction (MI), did not express VEGFR2 (D, enlarged in E–G; I–K). Medium-power view of VEGFR2+ capillaries (H). Emcn (A and D–J) and endoglin/CD105 (L) were highly upregulated in endocardium and expressed in subendocardial vessels. Cx40-EGFP was expressed in preexisting coronary arteries (shown in uninjured heart, M), but not in de novo subendocardial vessels (N), consistent with a nonarterial origin. Cx40-EGFP is expressed in Purkinje fibers (white arrowheads, N and O), and these were displaced around forming subendocardial vessels in MI (yellow arrowheads, O) but not uninjured, hearts (N). In the PdgfbCreERT2; R26R-EYFP reporter line, the endocardium (arrowheads, Q) and all endothelial cells of subendocardial vessels formed after MI were entirely negative for EYFP (P–R), confirming their derivation from a cell type that did not express Pdgfb/EYFP prior to MI. Representative of n = 15 WT MI hearts (n = 4 sham); PdgfbCreERT2 × R26R-EYFP hearts: n = 4 MI hearts (n = 3 sham); Cx40-EGFP: n = 6 MI hearts (n = 3 sham). epi, epicardium; endo, endocardium; CA, coronary artery; CV, coronary vein; myo, myocardium; PF, Purkinje fiber. Scale bars: 200 μm (A and D); 100 μm (L, M, and O); 50 μm (B, E–H, N, and P–R); 20 μm (C and I–K).

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