Hypoxia activates placental growth factor expression in lymphatic endothelial cells

// Laura Tudisco 1 , Augusto Orlandi 2 , Valeria Tarallo 1, * and Sandro De Falco 1, * 1 Angiogenesis LAB, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, CNR, Naples, Italy 2 Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy * These authors have contributed equally to this work Correspondence to: Sandro De Falco, email: sandro.defalco@igb.cnr.it Valeria Tarallo, email: valeria.tarallo@igb.cnr.it Keywords: hypoxia, PlGF, VEGF family, lymphatic cells, colorectal cancer Received: December 14, 2016     Accepted: February 08, 2017     Published: March 02, 2017 ABSTRACT Placental growth factor (PlGF), a proangiogenic member of vascular endothelial growth family, is active during pathological conditions like cancer, metastasis formation and hind limb ischemia and in wound healing. Endothelial cells express PlGF and hypoxia positively modulates in vitro its expression. To verify whether hypoxia modulates PlGF expression in different cellular contexts and in vivo , we first analyzed five human and five mouse cancer cell lines showing that in eight of them hypoxia positively modulates PlGF. Next, we analyzed xenograft colorectal cancer tumors showing that human cancer cells were able to express PlGF in hypoxic area of the tumor. Surprisingly, we did not visualize mouse PlGF in CD31 positive tumor vessels, but in low CD31 positive vessels, a characteristic of lymphatic vessels. We found that hypoxia effectively activates PlGF expression in lymphatic endothelial cells as well as in LYVE1 positive tumor vessels. We also investigated two additional mouse angiogenic models, hind limb ischemia and wound healing, and we confirmed that lymphatic vessels of both ischemic muscles and skin express PlGF. These results show for the first time that hypoxia activates PlGF expression in lymphatic endothelial cells, which have to be considered an additional source for PlGF production in pathological contexts.