Involvement of COX‐2/PGE₂ signalling in hypoxia‐induced angiogenic response in endothelial cells

Abstract

To evaluate the impact of hypoxia on the angiogenic capability of endothelial cells (ECs), and further investigate whether the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) signalling is involved in the angiogenic response of ECs to hypoxia. We explored the impact of various periods (1, 3, 6, 12, 24 hrs) of hypoxia (2% O2) on human umbilical vein endothelial cells (HUVECs) in vitro. We observed cell viability, migration, tube formation, analysed COX-2, vascular endothelial growth factor (VEGF), AQP1 mRNA transcription, protein expression and measured PGE2, VEGF protein concentration in cell supernatants. Then we treated HUVECs with COX-2 selective inhibitor NS398, EP1/2 combined antagonist AH6809 and exogenous PGE2 to investigate the role of COX-2/PGE2 signalling in the angiogenic response of ECs to hypoxia. The results demonstrated that short-term hypoxic treatment enhanced HUVECs proliferation, migration, tube formation, significantly up-regulated COX-2, VEGF, AQP1 mRNA level, protein expression and promoted PGE2, VEGF release. The pharmacological inhibition study revealed that exposure of HUVEC to NS398 and AH6809 under hypoxia impaired the biological responses of ECs to hypoxia. Exogenous PGE2 augments the effects of hypoxia on HUVECs, and partially reversed the inhibitory effects of NS398 on HUVECs proliferation and angiogenic capability. Short-term hypoxic treatment enhanced angiogenic capability of ECs, and COX-2/PGE2 signalling may play a critical role in the biological response of ECs to hypoxia.

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

“…The COX-2/PGE2 axis is a potential driver of HIF-2α expression and activity in HCC cells and HCC tissues under hypoxic conditions COX-2 is also upregulated in hypoxic HCC tissues and is associated with a poor prognosis in HCC patients; this relationship with HCC is similar to that of HIF-2α (10,11,16,18). COX-2 elicits its effects mainly through producing prostaglandins, especially PGE2 (20,21).…”

“…Previous studies have also revealed that COX-2 can be induced by various stimuli, including hypoxia (15,16). In the context of HCC, COX-2 expression in tumour tissues is closely associated with the spontaneous initiation, development and treatment effects of HCC (17)(18)(19).…”

Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

“…Another candidate is COX2 (cyclooxygenase 2), a target gene of NF-B (40). Prostaglandin E2, a product of COX2, increases microvascular permeability (41), and activation of the COX2/PGE2 pathway increases AQP1 mRNA expression in human umbilical vein endothelial cells (42).…”

Red ginseng represses hypoxia-induced cyclooxygenase-2 through sirtuin1 activation

“…Most solid tumors exhibit inflammatory properties characterized by increased levels of prostaglandins (Stasinopoulos et al 2013). Cyclooxygenase-2 (COX-2) is induced by the hypoxic microenvironment (Fredenburgh et al 2009;Kaidi et al 2006;Lee et al 2010;Zhao et al 2012). COX-2 increases metastatic potential in cancer cells and silencing of COX-2 inhibits metastasis and delays tumor onset of poorly differentiated metastatic cancer cells (Stasinopoulos et al 2013;Tsujii et al 1997).…”