Hypoxia Regulates Vascular Endothelial Growth Factor Gene Expression in Endothelial Cells

Abstract

Vascular endothelial growth factor (VEGF) is a potent mitogen specific for endothelial cells. Its expression is dramatically induced by low oxygen tension in a variety of cell types, and it has been suggested to be a key mediator of hypoxia-induced angiogenesis. Although VEGF action is targeted to endothelial cells, it is generally believed that these cells do not express VEGF. In addition, the mechanisms by which hypoxia regulates VEGF production remain unclear. We report in the present study that pulmonary artery endothelial cells do not express VEGF under basal conditions; however, significant VEGF mRNA levels accumulate when these cells are exposed to hypoxia. Using a DNA fragment containing human VEGF promoter sequence, we identified a 28-bp element that is necessary and sufficient to upregulate transcription in response to hypoxia. This element can act as a hypoxia-specific enhancer when placed upstream or downstream from a heterologous promoter. The enhancer includes, in addition to an octamer homologous to the hypoxia-inducible factor-1 (HIF-1) consensus, a sequence that resides 3' to the consensus. Although this sequence may not be involved in the binding of HIF-1, it is absolutely required for the enhancer activity and may be the binding site for certain constitutive binding proteins. The expression of VEGF by endothelial cells in response to hypoxia may provide an important mechanism by which endothelial cell permeability and proliferation is regulated in an autocrine manner.

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade

“…One such factor, HIF-1, mediates a response to hypoxia partly through the transcriptional activation of several genes including VEGF. [58][59][60] Increased expression of HIF-1a in rat and human prostatic carcinoma cell lines is associated with increased cell growth rates and metastatic potential. [61][62][63] In addition, HIF-1a is also expressed in normoxic cancer cells, suggesting that HIF-1a may be dysregulated in prostate cancer and thus drive the transcription of hypoxia-adaptive genes such as VEGF.…”

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

“…Among the growth factors involved in tumour angiogenesis, vascular endothelial growth factor (VEGF) has been identified as a leading pro-angiogenic candidate [3]. The production of VEGF is controlled through the cellular response to low oxygen levels (hypoxia) which activate the transcription of VEGF by increasing the formation of reactive oxygen species (ROS) [4][5].…”

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

“…By contrast, under hypoxia or in the presence of iron chelators, the degradation of HIF-1α is prevented [7,11,12]. As a result, this stabilization initiates a multi-step pathway of activation of HIF-1α that includes hypoxia-dependent nuclear translocation and dimerization with ARNT to interact with hypoxia responwww.cell-research.com | Cell Research Qi Fang Li et al 549 npg sive element (HRE) of target genes such as erythropoietin (EPO) [13], vascular endothelial growth factor (VEGF) [14], inducible nitric-oxide synthase [15], heme oxygenase 1 [16], and so on. Taken together, it comes as no surprise that the HIF-dependent hypoxic response pathway plays a prominent role in mediating the consequences of many disease states, including cerebral and myocardial ischemia, pulmonary hypertension, and tumorigenesis [17].…”