Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs

*Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Public Health,
^‡Department of Cardiovascular Surgery, Qi Lu Hospital, Shandong University, Jinan 250012, Shandong Province, People's Republic of China; and
^†Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden

Communicated by Tadamitsu Kishimoto, Osaka University, Osaka, Japan, May 25, 2007 (received for review April 2, 2007)

Abstract

Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR-α is mainly involved in angiogenic synergism, whereas PDGFR-β mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.

Footnotes

^§To whom correspondence may be addressed. E-mail: zhangyun{at}sdu.edu.cn or yihai.cao{at}ki.se
Author contributions: H. Lu, X.X., and M.Z. contributed equally to this work; H. Lu, M.Z., Yun Zhang, and Y.C. designed research; H. Lu, X.X., M.Z., R.C., E.B., C.L., H. Lin, G.Y., H.S., L.Q., M.T., H.D., Yanen Zhang, R.S., and Y.B. performed research; Y.C. contributed new reagents/analytic tools; H. Lu, X.X., and R.C. analyzed data; and H. Lu, X.X., Yun Zhang, and Y.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0704966104/DC1.
Abbreviations:

αSMA,

α smooth muscle actin;

LAD,

left anterior descending;

LVEF,

left ventricle ejection fraction;

MBF,

myocardial blood flow;

WT,

wall thickening;

VSMC,

vascular smooth muscle cells;

vWF,

von Willebrand factor.
Freely available online through the PNAS open access option.