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Differential roles of PDGFR- and PDGFR-β in angiogenesis and vessel stability

Junhang Zhang^*,,1, Renhai Cao^,1, Yun Zhang, Tanghong Jia^||, Yihai Cao^,2 and Eric Wahlberg^*,2

^* Division of Vascular Surgery, Department of Molecular Medicine and Surgery, and

Laboratory of Angiogenesis Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;

Qilu Hospital and

^|| Clinical Medical College, Shandong University, Jinan, Shandong, China; and

Department of Developmental Biology, China Medical University; Liaoning Cancer Hospital and Institute, Shenyang, China

² Correspondence: E.W., Division of Vascular Surgery, Department of Molecular Medicine and Surgery, N1:06, Karolinska Institutet, SE-17176, Stockholm, Sweden. E-mail: eric.wahlberg{at}ki.se; Y.C., Laboratory of Angiogenesis Research, Microbiology, Tumor and Cell Biology, Nobels Väg16, Karolinska Institutet, SE-17177, Stockholm, Sweden. E-mail: yihai.cao{at}ki.se

Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arteriogenic factors. Using in vivo angiogenesis and ischemic hind-limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF-2) in combinations with PDGF-AA and PDGF-AB, two members of the platelet-derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF-AA/FGF-2 and PDGF-AB/FGF-2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF-2 up-regulates PDGFR- and -β expression levels in the newly formed blood vessels. Interestingly, PDGF-AB/FGF-2, but not PDGF-AA/FGF-2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti-PDGFR-β neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability. These findings demonstrate that PDGFR-β receptor is essential for vascular stability. Similarly, PDGF-AB/FGF-2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF-AB/FGF-2 leads to dramatic improvement of the paw’s skin perfusion. Immunohistochemical analysis of the treated skeletal muscles confirms that a combination of PDGF-AB and FGF-2 significantly induces arteriogenesis in the ischemic tissue. A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases.—Zhang, J., Cao, R., Zhang, Y., Jia, T., Cao, Y., Wahlberg, E. Differential roles of PDGFR- and PDGFR-β in angiogenesis and vessel stability.

Key Words: neovascularization • ischemia • growth factor • receptor

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