PDGF-CC underlies resistance to VEGF-A inhibition and combinatorial targeting of both suppresses pathological angiogenesis more efficiently

Abstract

// Lei Zheng 1, 2, * , Chen Zhao 3, * , Yuxiang Du 2 , Xianchai Lin 2 , Yida Jiang 2 , Chunsik Lee 2 , Geng Tian 1 , Jia Mi 1 , Xianglin Li 1 , Qishan Chen 2 , Zhimin Ye 2 , Lijuan Huang 2 , Shasha Wang 2 , Xiangrong Ren 2 , Liying Xing 2 , Wei Chen 2 , Delong Huang 1, 2 , Zhiqin Gao 4 , Shuping Zhang 1 , Weisi Lu 2 , Zhongshu Tang 2 , Bin Wang 5 , Rong Ju 2 , Xuri Li 1, 2 1 Center for Medical and Pharmaceutical Research, Binzhou Medical University, Yantai, Shandong, 264003, P. R. China 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, P. R. China 3 Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, P. R. China 4 Department of Cell Biology, Weifang Medical University, Weifang, 261053 P. R. China 5 Medical Imaging Institute, Shandong Province Characteristical Key Subject, Medical Imaging and Nuclear Medicine, Binzhou Medical University, Yantai, 264003 P. R. China * Equal first authors Correspondence to: Xuri Li, email: lixr6@mail.sysu.edu.cn Rong Ju, email: jurong@mail.sysu.edu.cn Bin Wang, email: binwang001@aliyun.com Keywords: angiogenesis, PDGF-CC, VEGF-A, drug resistance Received: May 11, 2016     Accepted: October 14, 2016     Published: October 24, 2016 ABSTRACT Anti-VEGF-A therapy has proven to be effective for many neovascular diseases. However, drug resistance to anti-VEGF-A treatment can develop. Also, not all patients with neovascular diseases are responsive to anti-VEGF-A treatment. The mechanisms underlying these important issues remain unclear. In this study, using different model systems, we found that inhibition of VEGF-A directly upregulated PDGF-CC and its receptors in multiple cell types in pathological angiogenesis in vitro and in vivo . Importantly, we further revealed that combinatorial targeting of VEGF-A and PDGF-CC suppressed pathological angiogenesis more efficiently than monotherapy. Given the potent angiogenic activity of PDGF-CC, our findings suggest that the development of resistance to anti-VEGF-A treatment may be caused by the compensatory upregulation of PDGF-CC, and combined inhibition of VEGF-A and PDGF-CC may have therapeutic advantages in treating neovascular diseases.