Dynamics of angiogenesis in ischemic areas of the infarcted heart

Koichi Kobayashi,Ryosuke Kikuchi,Toyoaki Murohara,Masanori Hirashima,Yoshihiro Morishita,Kengo Maeda,Mikito Takefuji

doi:10.1038/s41598-017-07524-x

Koichi Kobayashi, Ryosuke Kikuchi + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-07524-x

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Abstract

Cardiomyocytes are susceptible to apoptosis caused by hypoxia during the acute and subacute phases of myocardial infarction (MI). Angiogenesis can reduce MI-induced damage by mitigating hypoxia. It has been speculated that the ischemic border zone is a unique area rescued by angiogenic therapy. However, the mechanism and timing for new vessel formation in the mammalian heart following hypoxia are unclear. Identifying targets that benefit from angiogenesis treatment is indispensable for the development of revolutionary therapies. Here, we describe a novel circulatory system wherein new vessels develop from the endocardium of the left ventricle to perfuse the hypoxic area and salvage damaged cardiomyocytes at 3–14 days after MI by activating vascular endothelial growth factor signaling. Moreover, enhanced angiogenesis increased cardiomyocyte survival along the endocardium in the ischemic zone and suppressed ventricular remodeling in infarcted hearts. In contrast, cardiomyocytes in the border zone’s hypoxic area underwent apoptosis within 12 h of MI, and the border area that was amenable to treatment disappeared. These data indicate that the non-perfused area along the endocardium is a site of active angiogenesis and a promising target for MI treatment.

Highlights

Myocardial infarction (MI) is a leading cause of death in westernized countries
The hypoxyprobe staining weakened and disappeared in the area that was perfused with new vessels from the left ventricle (LV) (Fig. 1A), which increased dramatically over a broad area between days 3 and 4, and primitive bud-like vessels sprouted from the endocardium within the ischemic area of day 3 tissue (Fig. 1B)
Most newly developed therapies that involve angiogenic, anti-apoptotic factors, or specific cells have targeted the interface between the perfused and the non-perfused areas in the border zone, and they have tried to inhibit cardiomyocyte apoptosis or induce angiogenesis in this area

Summary

Introduction

Thrombolysis and subsequent catheter intervention therapy during the acute phase reduce the size of the infarct and improve the prognoses of MI patients[1, 2]. New treatments that use angiogenic or anti-apoptotic factors, and cell-based therapies are expected to alleviate heart damage. Clinical trials involving vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) have not yielded the expected results[3,4,5]; no effective or innovative therapies have been developed for MI since catheter intervention became a widely used treatment. One reason for the lack of adequate alternative therapies is that the target area and cells to be salvaged in the infarcted heart have not been identified, partly because MI patients typically have a variety of disease conditions.

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