Adenosine A
            <sub>2A</sub>
            receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Ahmad, Aftab; Ahmad, Shama; Glover, Louise; Miller, Stacy; Shannon, John M.; Guo, Xinhong; Franklin, Wilbur A.; Bridges, James P.; Schaack, Jerome; Colgan, Sean P.; White, Carl W.

doi:10.1073/pnas.0901326106

Cited by 124 publications

(107 citation statements)

References 66 publications

(70 reference statements)

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…39 Previous studies revealed that HIF-2a was associated with adora2a expression in endothelial and chromaffin cells. 29,40 In this study, we found the adora2a protein level and responsiveness to CGS21680 in immune cells were correlated with HIF-2a. Our results are important, not only because we reconfirmed the regulatory relationship between HIF-2a and adora2a in other cell types, but also because these findings provide new evidence and explanations to the well known "hypoxia-adenosinergic immunosuppression".…”

Section: Discussionmentioning

confidence: 77%

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Zhang

Han

Dai

et al. 2016

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2a in T/NKT cells and found that HIF-2a knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2a knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1 + cell depletion or Fas ligand blockade.Compared with wild-type NKT cells, HIF-2a 2/2 NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2a-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2a 2/2 NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2a in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2a-knockout mice. Taken together, our results reveal a hypoxia/HIF-2a/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.

show abstract

Section: Discussionmentioning

confidence: 77%

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Zhang

Han

Dai

et al. 2016

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Moreover, even though the expressions of A 2A AR and A 2B AR in HUVECs are well described [23,32,33], our data reinforce the importance of classifying into EOPE and LOPE when studying preeclampsia, as in this analysis; they presented important pathophysiological differences which seem to not have a relationship with gestational age. In this regard, and despite we have not studied the mechanisms linked with those differences, but considering that hypoxia upregulates A 2A AR expression in placental explants [31] and epithelial cells [34,35], it is interesting to speculate that the differences observed in the expression of A 2A AR in EOPE and LOPE might suggest different capacities to respond to hypoxia in those conditions. This hypothesis is reinforced by recent evidence [36] showing that villous explants extracted from EOPE and cultured under varying oxygen tensions exhibited reduced levels of hydroxylated hypoxia-inducible factor type 1 alpha, a phenomenon that was absent in LOPE.…”

Section: Discussionmentioning

confidence: 99%

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Escudero

Bertoglia

Hernadez

et al. 2012

Purinergic Signalling

View full text Add to dashboard Cite

To investigate whether fetal endothelial cell proliferation and migration are modulated by the A 2A adenosine receptor (A 2A AR), nitric oxide (NO) and the vascular endothelial growth factor (VEGF) signaling pathway, we isolated human umbilical vein endothelial cells from normal pregnancy (n023), preterm delivery (n04), and late-onset (LOPE, n010) and early-onset preeclampsia (EOPE, n08). We used the non-selective adenosine receptor agonist (NECA) and the selective agonist (CGS-21680) and/or selective antagonist (ZM-241385) for A 2A AR. Also, the nitric oxide synthase (NOS) inhibitor, L-NAME, was used in co-incubation with CGS-21680. Compared to normal pregnancy, EOPE exhibited low cell proliferation and migration associated with reduced expressions of A 2A AR and VEGF and NO synthesis (i.e., total and phosphorylated serine 1177 endothelial NOS and nitrite formation). In contrast, LOPE exhibited the opposite behavior in all these markers compared to normal pregnancy or EOPE. Cell proliferation and migration were increased by CGS-21680 (or NECA) in all analyzed groups (EOPE>LO-PE>normal pregnancy) compared to their respective basal conditions, an effect that was associated with high NO and VEGF synthesis and blocked by ZM-241385 with significantly different IC 50 for each group (EOPE>LOPE>normal pregnancy). The differences seem independent of gestational age.L-NAME blocked the CGS-21680-mediated cell proliferation and migration in normal pregnancy and LOPE (IC 50 036.2± 2.5 and 8.6±2.2 nM, respectively) as well as the VEGF expression in normal pregnancy. Therefore, the A 2A AR/NO/ VEGF signaling pathway exhibits a pro-angiogenic effect in normal pregnancies and LOPE, whereas impairment in this pathway seems related to the reduced angiogenic capacity of the fetal endothelium in EOPE.

show abstract

“…Hypoxia is known to increase cytosolic calcium (26) and has been shown to up-regulate calpain protease activity in several cell types, such as pulmonary arterial endothelial cells (27). The ability of calpain to cleave FLNA is also regulated by phosphorylation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Several kinases, including PKA, Pak1, and RSK, as well as phosphatases such as calcineurin, have been proposed to regulate FLNA phosphorylation (10).…”

Section: Discussionmentioning

confidence: 99%

“…2 D and E). We also analyzed the expression of previously described HIF-2α-specific target genes, such as Cyclin D2, p27, E2F1, A2AR, and CITED2 (12)(13)(14). Among these genes only CITED2 showed hypoxia-dependent induction in M2 and A7 cells (Fig.…”

Section: Down-regulation Of Flna Expression Inhibits the Hif Transactmentioning

confidence: 99%

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Zheng¹,

Zhou

Rouhi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a naturally occurring C-terminal fragment that accumulates in the cell nucleus. This fragment interacts with the N-terminal portion of HIF-1α spanning amino acid residues 1-390 but not with HIF-2α. In hypoxia this fragment facilitates the nuclear localization of HIF-1α, is recruited to HIF-1α target gene promoters, and enhances HIF-1α function, resulting in up-regulation of HIF-1α target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1α and potentiates angiogenesis and tumor progression.cancer | subcellular localization | signal transduction

show abstract

Adenosine A _2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Cited by 124 publications

References 66 publications

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Contact Info

Product

Resources

About

Adenosine A 2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Cited by 124 publications

References 66 publications

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Contact Info

Product

Resources

About

Adenosine A _2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells