Endothelial Deletion of Phospholipase D2 Reduces Hypoxic Response and Pathological Angiogenesis

• DOI: 10.1161/atvbaha.114.303416
• Publication Date: 2014-06-20T08:20:37Z
• Authors: Jaewang Ghim; Jin-Sook Moon; Chang Sup Lee; Junyeop Lee; Parkyong Song; Areum Lee; Jin-Hyeok Jang; Dayea Kim; Jong Hyuk Yoon; Young Jun Koh; Chaithanya Chelakkot; Byung Jun Kang; Jung-Min Kim; Kyung Lock Kim; Yong Ryoul Yang; Youngmi Kim; Sun-Hee Kim; Daehee Hwang; Pann-Ghill Suh; Gou Young Koh; Young-Yun Kong; Sung Ho Ryu
• Keywords: Cell Survival; 610; HIF-1-ALPHA; TUMOR ANGIOGENESIS; MECHANISMS; NORMALIZATION; angiogenesis; Carcinoma, Lewis Lung; Mice; 03 medical and health sciences; Cell Movement; BINDING; Human Umbilical Vein Endothelial Cells; Phospholipase D; Animals; Humans; phospholipase D2; Hypoxia; Cells, Cultured; GENE-EXPRESSION; Cell Proliferation; Mice, Knockout; 0303 health sciences; Neovascularization, Pathologic; Endothelial Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; 3. Good health; ALPHA; Mice, Inbred C57BL; Disease Models, Animal; hypoxia-inducible factor-1; Animals, Newborn; Gene Expression Regulation; endothelial cell; INDUCIBLE FACTORS; TRANSLATION; INHIBITORS

Objective— Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis that occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α and target genes are important for the angiogenic functions of ECs. Phospholipase D2 (PLD2) is a crucial signaling mediator that stimulates the production of the second messenger phosphatidic acid. PLD2 is involved in various cellular functions; however, its specific roles in ECs under hypoxia and in vivo angiogenesis remain unclear. In the present study, we investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo.

Approach and Results—

Pld2 knockout ECs exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of hypoxia-inducible factor-1α target genes, including VEGF , PFKFB3 , HMOX-1 , and NTRK2 . Consistent with this, PLD2 contributed to hypoxia-induced hypoxia-inducible factor-1α expression at the translational level. The roles of PLD2 in hypoxia-induced in vivo pathological angiogenesis were assessed using oxygen-induced retinopathy and tumor implantation models in endothelial-specific Pld2 knockout mice. Pld2 endothelial-specific knockout retinae showed decreased neovascular tuft formation, despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 endothelial-specific knockout mice.

Conclusions— Our findings demonstrate a novel role for endothelial PLD2 in the survival and migration of ECs under hypoxia via the expression of hypoxia-inducible factor-1α and in pathological retinal angiogenesis and tumor angiogenesis in vivo.