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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 29; pp. 12140 - 12145
• Main Authors: Lu, Huixia, Xu, Xinsheng, Zhang, Mei, Cao, Renhai, Bråkenhielm, Ebba, Li, Changjiang, Lin, Huili, Yao, Guihua, Sun, Huiwen, Qi, Lihang, Tang, Mengxiong, Dai, Hongyan, Zhang, Yanen, Su, Runyi, Bi, Yanwen, Zhang, Yun, Cao, Yihai
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.07.2007; National Acad Sciences
• Subjects: Angiogenesis; Angiogenesis Inducing Agents; Angiography; Animals; Biological Sciences; Blood vessels; Cells; Collateral Circulation - drug effects; Coronary Circulation - drug effects; Coronary vessels; Drug Therapy, Combination; Echocardiography; Endothelial cells; Fibroblast Growth Factor 2 - pharmacology; Heart; Heart - drug effects; Heart - physiopathology; Heart attacks; Heart ventricles; Hogs; Left coronary artery; Medical treatment; Medicin och hälsovetenskap; Mice; Models, Biological; Myocardial infarction; Myocardial Ischemia - chemically induced; Myocardial Ischemia - pathology; Myocardium; Platelet-Derived Growth Factor - pharmacology; Proteins; Proto-Oncogene Proteins c-sis; Renovations; Swine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704966104

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.