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Sustained Placental Growth Factor-2 Treatment Does Not Aggravate Advanced Atherosclerosis in Ischemic Cardiomyopathy

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Abstract

Angiogenic growth factor therapy for ischemic cardiovascular disease carries a risk of stimulating atherosclerotic plaque growth. We evaluated risk benefit ratio of sustained administration of recombinant human placental growth factor (rhPlGF)-2 in mice with advanced atherosclerosis and chronic ischemic cardiomyopathy. We maintained apolipoprotein E-deficient mice on a high cholesterol diet and induced myocardial infarction by transient ligation at 4 weeks. At 8 weeks, we assessed left ventricular (LV) function and randomized mice to receive rhPlGF-2 or vehicle (VEH) subcutaneously for 28 days. Administration of rhPlGF-2 significantly increased PlGF plasma levels without adverse hemodynamic or systemic inflammatory effects. RhPlGF-2 did not increase plaque area, composition, or vulnerability in the aortic arch. RhPlGF-2 significantly improved contractile function and reduced LV end-systolic and end-diastolic volume indices with a concomitant increase in capillary and arteriolar density in ischemic myocardium. RhPlGF-2 may represent a promising therapeutic strategy in chronic ischemic cardiomyopathy.

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Abbreviations

Apo E−/− :

Apolipoprotein E knockout

EF:

Ejection fraction

ESVi/EDVi:

End-systolic/diastolic volume index

hsCRP:

High-sensitivity C-reactive protein

ICAM:

Intercellular adhesion molecule

IL:

Interleukin

LV:

Left ventricle

MAP:

Mean arterial pressure

MI:

Myocardial infarction

PBS:

Phosphate-buffered saline

PRSW:

Preload-recruitable stroke work

rhPlGF:

Recombinant human placental growth factor

SBP/DBP:

Systolic/diastolic blood pressure

TPR:

Total peripheral resistance

VCAM:

Vascular cell adhesion molecule

VEGF(R):

Vascular endothelial growth factor (receptor)

VEH:

Vehicle

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Acknowledgements

We thank Prof. Dr. Aernout Luttun for helpful advice and Dr. Ann Belmans for her assistance with statistical analyses.

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Authors and Affiliations

  1. Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, 3000, Leuven, Belgium

    Ming Wu, Peter Pokreisz, Melissa Swinnen, Ellen Caluwe, Hilde Gillijns, Nina Vanden Driessche, Desire Collen & Stefan Janssens

  2. CoBioRes, NV, Leuven, Belgium

    Peter Pokreisz, Andrea Casazza & Desire Collen

  3. Department of Imaging and Pathology, KU Leuven, Leuven, Belgium

    Erik Verbeken

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  1. Ming Wu
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  2. Peter Pokreisz
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  10. Stefan Janssens
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Correspondence to Stefan Janssens.

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Sources of Funding

This work was supported by a KU Leuven Program Financing grant (PF 10/014) to Dr. S. Janssens, by a dedicated grant of Life Science Research Partners VZW, a non-profit organization for the advancement of biomedical science and by a postdoctoral grant of the Fund for Scientific Research Flanders to Dr. P. Pokreisz (1246510N) and to Dr. Swinnen (12B8212N). Prof. Janssens holds a Chair in Cardiology sponsored by Astra Zeneca and a Bayer SA-NV Chair in Cardiovascular Medicine.

Disclosures

D.C. is a chairman of the board of CoBioRes, NV, which could be perceived as conflict of interest. The other authors have declared that no conflict of interest exists.

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All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

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Associate Editor Joost Sluijter oversaw the review of this article

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Wu, M., Pokreisz, P., Swinnen, M. et al. Sustained Placental Growth Factor-2 Treatment Does Not Aggravate Advanced Atherosclerosis in Ischemic Cardiomyopathy. J. of Cardiovasc. Trans. Res. 10, 348–358 (2017). https://doi.org/10.1007/s12265-017-9742-4

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