Low oxygen tension primes aortic endothelial cells to the reparative effect of tissue-protective cytokines

Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared to 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis

ERYTHROPOIETIN FOR THE TREATMENT OF SUBARACHNOID HEMORRAGE: A FEASIBLE INGREDIENT FOR A SUCCESS MEDICAL RECIPE

Subaracnhoid hemorrage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Althoug an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbility and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered fo the treatment of cerebral vasospasm. In recent years, the mechanism contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been intensively investigated. A number of pathological processes have been identified in the pathogenesis of vasospasm including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. to date, the current therapeutic interventions remain ineffective being limited to the manipulation os systemic blood pressure, variation of blood volume and viscosity, and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO), has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is systematically administered. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the recurrent review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrage

"<i>Festina lente</i>" — a multicenter study on the outcomes of carotid endarterectomy, depending on vessel suturing speed

Aim. Analysis of inhospital and long-term outcomes of conventional carotid endarterectomy (CEA) depending on vessel suturing speed.Material and methods. The present prospective multicenter study for the period from March 1, 2017 to October 1, 2020 included 2366 patients who underwent conventional CEA with patch angioplasty. Depending on the time required to apply 1 stitch, 4 groups of patients were formed: group 1 (n=471; 19,9%) — 1 stitch per 2 seconds; group 2 (n=865; 36,5%) — 1 stitch per 3 seconds; group 3 (n=692; 29,2%) — 1 stitch per 4 seconds; group 4 (n=338; 14,3%) — 1 stitch per 5 seconds. The term "stitch" refers to two needle punctures. The follow-up postoperative period was 18,5±11,0 months.Results. There were no deaths and myocardial infarctions (MI) in the inhospital postoperative period. In group 1, anastomotic bleeding (n=93; 19,7%; p&lt;0,0001) and stroke (n=3; 0,63%; p=0,02) due to internal carotid artery (ICA) thrombosis were more common. In the long-term follow-up period, there were no significant differences in mortality and MI rates. However, ICA restenosis requiring repeated CEA (n=37; 7,85%; p&lt;0,0001) and related stroke/transient ischemic attack (n=13; 2,8%; p=0,0001) were more often diagnosed in 1 group of patients. According to Kaplan-Meier curves, restenosis was most often revealed 6 months after CEA in the general sample.Conclusion. 1. Vessel suturing at a speed of 1 stitch per 2 seconds is associated with an increased risk of intraoperative ICA thrombosis, bleeding along the anastomosis, stroke, as well as restenosis and stroke in the long-term follow-up period. 2. Vessel suturing at a speed of 1 stitch per 5 seconds is not accompanied by an increase in inhospital stroke rate, despite the maximum ICA occlusion time relative to other groups of patients. 3. Vessel suturing at a speed of 1 stitch per 3 or 4 seconds characterized by the lowest incidence of all complications at the inhospital and long-term stages of postoperative follow-up

The Receptor That Tames the Innate Immune Response

Tissue injury, hypoxia and significant metabolic stress activate innate immune responses driven by tumor necrosis factor (TNF)-α and other proinflammatory cytokines that typically increase damage surrounding a lesion. In a compensatory protective response, erythropoietin (EPO) is synthesized in surrounding tissues, which subsequently triggers antiinflammatory and antiapoptotic processes that delimit injury and promote repair. What we refer to as the sequelae of injury or disease are often the consequences of this intentionally discoordinated, primitive system that uses a “scorched earth” strategy to rid the invader at the expense of a serious lesion. The EPO-mediated tissue-protective system depends on receptor expression that is upregulated by inflammation and hypoxia in a distinctive temporal and spatial pattern. The tissue-protective receptor (TPR) is generally not expressed by normal tissues but becomes functional immediately after injury. In contrast to robust and early receptor expression within the immediate injury site, EPO production is delayed, transient and relatively weak. The functional EPO receptor that attenuates tissue injury is distinct from the hematopoietic receptor responsible for erythropoiesis. On the basis of current evidence, the TPR is composed of the β common receptor subunit (CD131) in combination with the same EPO receptor subunit that is involved in erythropoiesis. Additional receptors, including that for the vascular endothelial growth factor, also appear to be a component of the TPR in some tissues, for example, the endothelium. The discoordination of the EPO response system and its relative weakness provide a window of opportunity to intervene with the exogenous ligand. Recently, molecules were designed that preferentially activate only the TPR and thus avoid the potential adverse consequences of activating the hematopoietic receptor. On administration, these agents successfully substitute for a relative deficiency of EPO production in damaged tissues in multiple animal models of disease and may pave the way to effective treatment of a wide variety of insults that cause tissue injury, leading to profoundly expanded lesions and attendant, irreversible sequelae