LABORATORY INVESTIGATION Correlation of Hypoxia-Inducible Factor 1a with Angiogenesis in Liver Tumors After Transcatheter Arterial Embolization in an Animal Model Bin Liang • Chuan-Sheng Zheng • Gan-Sheng Feng • Han-Ping Wu • Yong Wang • Hui Zhao • Jun Qian • Hui-Min Liang Received: 2 September 2009 / Accepted: 6 November 2009 / Published online: 24 November 2009 Ó Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2009 Abstract This study sought to determine the expression of hypoxia-inducible factor 1a (HIF-1a) and its relation to angiogenesis in liver tumors after transcatheter arterial embolization (TAE) in an animal model. A total of 20 New Zealand White rabbits were implanted with VX2 tumor in liver. TAE-treated group animals (n = 10) received TAE with polyvinyl alcohol particles. Control group animals (n = 10) received sham embolization with distilled water. Six hours or 3 days after TAE, animals were humanely killed, and tumor samples were collected. Immunohisto- chemical staining was performed to evaluate HIF-1a and vascular endothelial growth factor (VEGF) protein expres- sion and microvessel density (MVD). Real-time polymerase chain reaction was performed to examine VEGF mRNA levels. The levels of HIF-1a protein were significantly higher in TAE-treated tumors than those in the control tumors (P = 0.001). HIF-1a protein was expressed in via- ble tumor cells that were located predominantly at the periphery of necrotic tumor regions. The levels of VEGF protein and mRNA, and mean MVD were significantly increased in TAE-treated tumors compared with the control tumors (P = 0.001, 0.000, and 0.001, respectively). HIF-1a protein level was significantly correlated with VEGF mRNA (r = 0.612, P = 0.004) and protein (r = 0.554, P = 0.011), and MVD (r = 0.683, P = 0.001). We con- clude that HIF-1a is overexpressed in VX2 tumors treated with TAE as a result of intratumoral hypoxia generated by the procedure and involved in activation of the TAE-asso- ciated tumor angiogenesis. HIF-1a might represent a promising therapeutic target for antiangiogenesis in com- bination with TAE against liver tumors. Keywords Hypoxia-inducible factor 1a Á Angiogenesis Á Pathologic Á Embolization Á Therapeutic Á Liver neoplasms Á Experimental Introduction Transcatheter arterial embolization (TAE) is a well-estab- lished procedure for patients with unresectable primary and metastatic liver tumors [1]. On the basis of the initial observation that hepatic malignant lesions receive most (90–100%) of their blood supply from the hepatic artery [2], embolization of the tumor-feeding vessel may induce ischemia and hypoxia within the tumor and subsequent tumor necrosis, therefore achieving the tumor control [3]. However, recent studies have shed light on the implications of TAE-induced hypoxia in liver tumors. In studies evalu- ating TAE and angiogenesis, increased vascular endothelial growth factor (VEGF) and microvessel density (MVD) were reported in liver tumors after TAE [4–6], which suggests that angiogenesis is initiated in the residual viable tumor and may have an adverse effect on the therapeutic efficacy of TAE. Although the stimulation of tumor angiogenesis is attributed to hypoxia generated by TAE [7], the mechanism of the hypoxia-induced angiogenesis is not well understood. One way that cells respond to hypoxia is through a transcription factor, hypoxia-inducible factor 1 (HIF-1). B. Liang Á C.-S. Zheng (&) Á G.-S. Feng Á Y. Wang Á H. Zhao Á J. Qian Á H.-M. Liang Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie-fang Road, Wuhan 430022, People’s Republic of China e-mail: hqzcsxh@sina.com H.-P. Wu Department of Radiology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA 123 Cardiovasc Intervent Radiol (2010) 33:806–812 DOI 10.1007/s00270-009-9762-9