Study on the roles of endothelial PLD2 in hypoxic response and pathological angiogenesis

Abstract

Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α (HIF-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, I investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Here, I report that Pld2 knockout (KO) endothelial cells exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. 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 KO mice (eKO). Pld2 eKO retinae showed decreased neovascular tuft formation despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 eKO. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of HIF-1α target genes including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced HIF-1α expression at the translational level. Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α (HIF-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, I investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Here, I report that Pld2 knockout (KO) endothelial cells exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. 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 KO mice (eKO). Pld2 eKO retinae showed decreased neovascular tuft formation despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 eKO. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of HIF-1α target genes including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced HIF-1α expression at the translational level.