Hypoxia impairs agonist-induced integrin αIIbβ3 activation and platelet aggregation

Abstract

Under ischemic conditions, tissues are exposed to hypoxia. Although human physiology, to a certain extent, can adapt to hypoxic conditions, the impact of low oxygen levels on platelet function is unresolved. Therefore, we explored how reduction of atmospheric oxygen levels to 1% might affect agonist-induced aggregation and static adhesion of isolated human platelets. We uncovered that isolated, washed human platelets exposed to hypoxic conditions show reduced thrombin receptor-activating peptide-6 (TRAP-6) and convulxin-induced aggregation. Of note, this hypoxia-triggered effect was not observed in platelet-rich plasma. Independent of the agonist used (TRAP-6, ADP), activation of the platelet fibrinogen receptor integrin αIIbβ3 (GPIIbIIIa, CD41/CD61) was strongly reduced at 1% and 8% oxygen. The difference in agonist-induced integrin αIIbβ3 activation was apparent within 5 minutes of stimulation. Following hypoxia, re-oxygenation resulted in the recovery of integrin αIIbβ3 activation. Importantly, platelet secretion was not impaired by hypoxia. Static adhesion experiments revealed decreased platelet deposition to fibrinogen coatings, but not to collagen or vitronectin coatings, indicating that specifically the function of the integrin subunit αIIb is impaired by exposure of platelets to reduced oxygen levels. Our results reveal an unexpected effect of oxygen deprivation on platelet aggregation mediated by the fibrinogen receptor integrin αIIbβ3.

Hypoxia Modulates Platelet Purinergic Signalling Pathways

“…They reported that platelets exposed to extreme hypoxia had reduced expression of activated α IIb β 3 in response to ADP stimulation. 46 Our proposed model of hypoxia-induced alterations to purinergic signalling may offer a mechanistic explanation to these findings since an increase in VASP phosphorylation would attenuate P2Y 12 activity and reduce ADP-induced activation of α IIb β 3 . [47][48][49] Kiouptsi et al also demonstrated that brief, extreme hypoxic exposure (1% oxygen, 30 minutes) reduced aggregation of hypoxic washed platelets in response to TRAP-6.…”

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

“…Data from WASP −/− mice showed that integrin αIIbβ3 outside-in signaling, such as fibrinogen and JON/A binding under agonist stimulation, is normal, whereas integrin αIIbβ3 outside-in signaling-dependent events, such as spreading on immobilized fibrinogen, fibrin clot retraction, and rebleeding, are impaired [180]. Some extracellular materials, pathogens, and other factors, such as amyloid-β [185], UV [186], Mucor circinelloides [187], heparin [188], and hypoxia [189], also regulate αIIbβ3 signaling. Peroxisome proliferator-activated receptor γ (PPARγ) [190], reelin [191, 192], and disulfide isomerase [193] were also reported to be involved in integrin αIIbβ3 outside-in signaling.…”

Temporal transcriptome analysis suggest modulation of multiple pathways and gene network involved in cell-cell interaction during early phase of high altitude exposure

“…Identification of membrane glycoproteins like GP9, GP6, GP4 and integrin subunits like ITGA2B, ITGB3 has been reported in study in which volunteers exposed to continuous hypobaric hypoxia. Activation of membrane glycoproteins and integrin involvement has important role in platelet signalling and thrombosis [39,40]. In our study, activation was reflected during day7 of temporal analysis.…”