In situ photodeposition of ultra-small palladium particles on TiO2.

In situ and operando investigation of photocatalysts plays a fundamental role in understanding the processes of active phase formation and the mechanisms of catalytic reactions, which is crucial for the rational design of more efficient materials. Using a custom-made operando photocatalytic cell, an in situ procedure to follow the formation steps of Pd/TiO2 photocatalyst by synchrotron-based X-ray absorption spectroscopy (XAS) is proposed. The procedure resulted in the formation of ∼1 nm Pd particles with a much narrower size distribution and homogeneous spreading over TiO2 support compared with the samples generated in a conventional batch reactor. The combination of in situ XAS spectroscopy with high-angle annular dark-field scanning transmission electron microscopy demonstrated the formation of single-atom Pd(0) sites on TiO2 as the initial step of the photodeposition process. Palladium hydride particles were observed for all investigated samples upon exposure to formic acid solutions.

Enhanced Hydrogen Bonding by Urea Functionalization Tunes the Stability and Biological Properties of Peptide Amphiphiles.

Self-assembled nanostructures such as those formed by peptide amphiphiles (PAs) are of great interest in biological and pharmacological applications. Herein, a simple and widely applicable chemical modification, a urea motif, was included in the PA's molecular structure to stabilize the nanostructures by virtue of intermolecular hydrogen bonds. Since the amino acid residue nearest to the lipid tail is the most relevant for stability, we decided to include the urea modification at that position. We prepared four groups of molecules (13 PAs in all), with varying levels of intermolecular cohesion, using amino acids with distinct ß-sheet promoting potential and/or containing hydrophobic tails of distinct lengths. Each subset contained one urea-modified PA and nonmodified PAs, all with the same peptide sequence. The varied responses of these PAs to variations in pH, temperature, counterions, and biologically related proteins were examined using microscopic, X-ray, spectrometric techniques, and molecular simulations. We found that the urea group contributes to the stabilization of the morphology and internal arrangement of the assemblies against environmental stimuli for all peptide sequences. In addition, microbiological and biological studies were performed with the cationic PAs. These assays reveal that the addition of urea linkages affects the PA-cell membrane interaction, showing the potential to increase the selectivity toward bacteria. Our data indicate that the urea motif can be used to tune the stability of a wide range of PA nanostructures, allowing flexibility on the biomaterial's design and opening a myriad of options for clinical therapies.

Adenosine promoted angiogenesis mediated by the release of small extracellular vesicles from human endothelial progenitor cells.

Endothelial progenitor cells (EPCs) are stem cells mainly derived from bone marrow; from where they migrate to repair and regenerate damaged tissues. eEPCs have been classified into two sub-populations, early (eEPC) and late EPCs (lEPC), depending on maturation stages in vitro. In addition, eEPC release endocrine mediators, including small extracellular vesicles (sEVs), which in turn may enhance the eEPC-mediated wound healing properties. Nevertheless, adenosine contributes to angiogenesis by recruiting eEPC at the injury site. However, whether ARs may enhance the secretome of eEPC, including sEVs, is unknown. Therefore, we aimed to investigate whether AR activation increase the release of sEVs in eEPC, which in turn has paracrine effects on recipient endothelial cells. Results shown that 5'-N-ethylcarboxamidoadenosine (NECA), a non-selective agonist, increase both the protein levels of the vascular endothelial growth factor (VEGF), and the number of sEVs released to the conditioned medium (CM) in primary culture of eEPC. Importantly, CM and EVs harvested from NECA-stimulated eEPC promote in vitro angiogenesis, without changes in cell proliferation, in recipient ECV-304 endothelial cells. This constitutes the first evidence showing that adenosine enhances sEVs release from eEPC, which has pro-angiogenic capacity on recipient endothelial cells.

Stability and Reversible Oxidation of Sub-Nanometric Cu5 Metal Clusters: Integrated Experimental Study and Theoretical Modeling.

Sub-nanometer metal clusters have special physical and chemical properties, significantly different from those of nanoparticles. However, there is a major concern about their thermal stability and susceptibility to oxidation. In situ X-ray Absorption spectroscopy and Near Ambient Pressure X-ray Photoelectron spectroscopy results reveal that supported Cu5 clusters are resistant to irreversible oxidation at least up to 773 K, even in the presence of 0.15 mbar of oxygen. These experimental findings can be formally described by a theoretical model which combines dispersion-corrected DFT and first principles thermochemistry revealing that most of the adsorbed O2 molecules are transformed into superoxo and peroxo species by an interplay of collective charge transfer within the network of Cu atoms and large amplitude "breathing" motions. A chemical phase diagram for Cu oxidation states of the Cu5 -oxygen system is presented, clearly different from the already known bulk and nano-structured chemistry of Cu.

Language Impairment in Children of Mothers with Gestational Diabetes, Preeclampsia, and Preterm Delivery: Current Hypothesis and Potential Underlying Mechanisms : Language Impartment and Pregnancy Complications.

Many conditions may impair or delay language development, including socioeconomic status, parent's education, or intrauterine environment. Accordingly, increasing evidence has described that pregnancy complications, including gestational diabetes mellitus (GDM), preeclampsia, and preterm delivery, are associated with the offspring's impaired neurodevelopment. Since language is one of the high brain functions, alterations in this function are another sign of neurodevelopment impairment. How these maternal conditions may generate language impairment has yet to be entirely understood. However, since language development requires adequate structural formation and function/connectivity of the brain, these processes must be affected by alterations in maternal conditions. However, the underlying mechanisms of these structural alterations are largely unknown. This manuscript critically analyzes the literature focused on the risk of developing language impairment in children of mothers with GDM, preeclampsia, and preterm delivery. Furthermore, we highlight potential underlying molecular mechanisms associated with these alterations, such as neuroinflammatory and metabolic and cerebrovascular alterations.

Maternal and Fetal Expression of ATP-Binding Cassette and Solute Carrier Transporters Involved in the Brain Disposition of Drugs.

Evidence from preclinical and clinical studies demonstrate that pregnancy is a physiological state capable of modifying drug disposition. Factors including increased hepatic metabolism and renal excretion are responsible for impacting disposition, and the role of membrane transporters expressed in biological barriers, including the placental- and blood-brain barriers, has received considerable attention. In this regard, the brain disposition of drugs in the mother and fetus has been the subject of studies attempting to characterize the mechanisms by which pregnancy could alter the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters. This chapter will summarize findings of the influence of pregnancy on the maternal and fetal expression of ABC and SLC transporters in the brain and the consequences of such changes on the disposition of therapeutic drugs.

COVID-19 on Pregnancy Outcomes, Mental Health and Placenta: Focus in Latin America.

The COVID-19 pandemic has impacted many aspects of health and society worldwide. One vulnerable group that faced SARS-CoV-2 infection is pregnant women, who were considered to have potentiated risk factors. In physiological pregnancy, maternal systems have several changes and adaptations to support fetal development. These changes involve regulations of cardiovascular, respiratory, and immunologic systems, among others, which SARS-CoV-2 could severely alter. Furthermore, the systemic effects of viral infection could be associated with placental dysfunction and adverse pregnancy outcomes, which have been studied from the start of the pandemic to date. Additionally, pregnancy is a condition of more significant mental health vulnerability, especially when faced with highly stressful situations. In this chapter, we have collected information on the effect of COVID-19 on maternal mortality, the SARS-CoV-2 infection rate in pregnancy, and the impact on pregnancy outcomes, maternal mental health, and placental function, with a particular focus on studies that consider the Latin American population.

The Placental Function Beyond Pregnancy: Insights from Latin America.

Currently, more than 100,000 papers had been published studying the placenta in both physiological and pathological contexts. However, relevant health conditions affecting placental function, mostly found in low-income countries, should be evaluated deeper. This review will raise some - of what we think necessary - points of discussion regarding challenging topics not fully understood, including the paternal versus maternal contribution on placental genes imprinting, placenta-brain communication, and some environmental conditions affecting the placenta. The discussions are parts of an international effort to fulfil some gaps observed in this area, and Latin-American research groups currently evaluate that.

Extracellular vesicles released upon stimulation with antiphospholipid antibodies: An actual direct procoagulant mechanism or a new factor in the lupus anticoagulant paradox?

Antiphospholipid antibodies (aPL) lead to a hypercoagulable state in vivo. Paradoxically, some of these autoantibodies perform as inhibitors of the coagulation cascade in vitro (a phenomenon referred to as "lupus anticoagulant"). The presence of lupus anticoagulant has been related to an increased quantity of plasma extracellular vesicles, which may constitute a direct procoagulant mechanism in antiphospholipid syndrome. This study investigates whether or not endothelial cell-derived extracellular vesicles released upon stimulation with aPL (aPL-EDEVs) are related to a higher direct coagulation activity. Using an in vitro model of endothelium, flow cytometry and a recalcified plasma-based assay, we found that the coagulation activity of aPL-EDEVs is mainly conditioned by the lupus anticoagulant-like activity of autoantibodies. Nevertheless, in the presence of ß2 glycoprotein I, a cofactor of aPL during the stimulation of endothelial cells, the coagulation activity of EDEVs is restored in a mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)-dependent manner. This phenomenon was especially evident when using immunoglobulins G from patients with vascular and obstetric primary antiphospholipid syndrome who manifest refractoriness to treatment. Our findings suggest that the role of aPL-EDEVs in the antiphospholipid syndrome-related hypercoagulable state may not rely on their capacity to enhance clotting directly. While ß2 glycoprotein I performs as a procoagulant cofactor and restores the coagulation activity of extracellular vesicles via MEK1/2 pathway, proportionally, autoantibodies interact with aPL-EDEVs and exhaust their coagulation properties. Further analysis is required to establish whether lupus anticoagulant-like autoantibodies opsonise extracellular vesicles and whether opsonised vesicles may lead to thrombosis by indirect means.

A robust quantitative approach for laser speckle contrast imaging perfusion analysis revealed anomalies in the brain blood flow in offspring mice of preeclampsia.

Microcirculation analysis of the brain cortex is challenging because surface perfusion varies rapidly in small space-time regions and is bone protected. The laser speckle contrast imaging (LSCI) technique allows analyzing in vivo brain vascular perfusion generating a large amount of data that requires sophisticated data analytics, making researchers invest much effort in processing. Our research question was whether the reduced placental perfusion model (RUPP) of preeclampsia (PE) was associated with impaired blood perfusion in the offspring's brains. We aimed to develop a robust numerical approach that mainly consisted of applying a signal-processing tool for calculating optimal segmentation and piece-wise fits of the offspring's brain perfusion signals obtained from the LSCI technique. We combined this tool with the usual statistical analysis, implementing both in Matlab software. We performed brain perfusion measurements from offspring (five days postnatal, P5) of control pregnant dams (sham, n = 13) and of RUPP dams (RUPP, n = 7) using the Pericam® PSI-HR system at a basal condition and after thermal stimuli (warm and cold). We found that pups of RUPP mice exhibited significant differences in perfusion and vascular response to thermal stimuli compared to the sham mice. These differences were associated with high data variability in the Sham group, while in the RUPP group, perfusion looks "stiffer." Data also suggest sex-dimorphism in the vascular response since female pups in the Sham group but not male pups showed statistically significant differences in response to the warm stimulus. Again, this sex-related difference was absent in pups of RUPP mice. In conclusion, we present a robust quantitative approach for LSCI measurements that revealed anomalies in the brain blood flow in offspring of the RUPP model of PE.

The cobalt oxidation state in preferential CO oxidation on CoOx/Pt(111) investigated by operando X-ray photoemission spectroscopy.

The combination of a reducible transition metal oxide and a noble metal such as Pt often leads to active low-temperature catalysts for the preferential oxidation of CO in excess H2 gas (PROX reaction). While CO oxidation has been investigated for such systems in model studies, the added influence of hydrogen gas, representative of PROX, remains less explored. Herein, we use ambient pressure scanning tunneling microscopy and ambient pressure X-ray photoelectron spectroscopy on a CoOx/Pt(111) planar model catalyst to analyze the active phase and the adsorbed species at the CoOx/Pt(111) interface under atmospheres of CO and O2 with a varying partial pressure of H2 gas. By following the evolution of the Co oxidation state as the catalyst is brought to a reaction temperature of above 150 °C, we determine that the active state is characterized by the transformation from planar CoO with Co in the 2+ state to a mixed Co2+/Co3+ phase at the temperature where CO2 production is first observed. Furthermore, our spectroscopy observations of the surface species suggest a reaction pathway for CO oxidation, proceeding from CO exclusively adsorbed on Co2+ sites reacting with the lattice O from the oxide. Under steady state CO oxidation conditions (CO/O2), the mixed oxide phase is replenished from oxygen incorporating into cobalt oxide nanoislands. In CO/O2/H2, however, the onset of the active Co2+/Co3+ phase formation is surprisingly sensitive to the H2 pressure, which we explain by the formation of several possible hydroxylated intermediate phases that expose both Co2+ and Co3+. This variation, however, has no influence on the temperature where CO oxidation is observed. Our study points to the general importance of a dynamic reducibility window of cobalt oxide, which is influenced by hydroxylation, and the bonding strength of CO to the reduced oxide phase as important parameters for the activity of the system.

Neurotrophic Keratitis in a Pediatric Patient With Goldenhar Syndrome and Trigeminal Aplasia Successfully Treated by Corneal Neurotization.

Herein, the authors report an unusual case of a 6-year-old boy with right-sided Goldenhar syndrome and trigeminal nerve aplasia who developed neurotrophic keratopathy (NK). Despite the use of therapeutic contact lenses and multiple temporary tarsorrhaphy, NK worsened showing a central corneal scar, neovascularization, and significant stromal thinning, with risk of corneal perforation. Cochet-Bonnet esthesiometry revealed complete corneal anesthesia. To minimize additional corneal complications, the patient underwent indirect corneal neurotization by a sural nerve autograft anastomosed to the contralateral supratrochlear nerve. At 24-month follow up, no epithelial defects, complications, or recurrence were observed. Significant improvements in corneal sensitivity with esthesiometry score of 20 mm and reflex blinking were achieved. This case highlights corneal anesthesia should be suspected among Goldenhar syndrome ophthalmologic abnormalities and monitored before corneal changes become irreversible. Since corneal neurotization can successfully improve corneal sensation, it could be considered as an early therapeutic option to avoid refractory NK.

The GPI-Anchored Protein Thy-1/CD90 Promotes Wound Healing upon Injury to the Skin by Enhancing Skin Perfusion.

Wound healing is a highly regulated multi-step process that involves a plethora of signals. Blood perfusion is crucial in wound healing and abnormalities in the formation of new blood vessels define the outcome of the wound healing process. Thy-1 has been implicated in angiogenesis and silencing of the Thy-1 gene retards the wound healing process. However, the role of Thy-1 in blood perfusion during wound closure remains unclear. We proposed that Thy-1 regulates vascular perfusion, affecting the healing rate in mouse skin. We analyzed the time of recovery, blood perfusion using Laser Speckle Contrast Imaging, and tissue morphology from images acquired with a Nanozoomer tissue scanner. The latter was assessed in a tissue sample taken with a biopsy punch on several days during the wound healing process. Results obtained with the Thy-1 knockout (Thy-1-/-) mice were compared with control mice. Thy-1-/- mice showed at day seven, a delayed re-epithelialization, increased micro- to macro-circulation ratio, and lower blood perfusion in the wound area. In addition, skin morphology displayed a flatter epidermis, fewer ridges, and almost no stratum granulosum or corneum, while the dermis was thicker, showing more fibroblasts and fewer lymphocytes. Our results suggest a critical role for Thy-1 in wound healing, particularly in vascular dynamics.

Loxin Reduced the Inflammatory Response in the Liver and the Aortic Fatty Streak Formation in Mice Fed with a High-Fat Diet.

Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN.

Secretome from Human Mesenchymal Stem Cells-Derived Endothelial Cells Promotes Wound Healing in a Type-2 Diabetes Mouse Model.

Tissue regeneration is often impaired in patients with metabolic disorders such as diabetes mellitus and obesity, exhibiting reduced wound repair and limited regeneration capacity. We and others have demonstrated that wound healing under normal metabolic conditions is potentiated by the secretome of human endothelial cell-differentiated mesenchymal stem cells (hMSC-EC). However, it is unknown whether this effect is sustained under hyperglycemic conditions. In this study, the wound healing effect of secretomes from undifferentiated human mesenchymal stem cells (hMSC) and hMSC-EC in a type-2 diabetes mouse model was analyzed. hMSC were isolated from human Wharton's jelly and differentiated into hMSC-EC. hMSC and hMSC-EC secretomes were analyzed and their wound healing capacity in C57Bl/6J mice fed with control (CD) or high fat diet (HFD) was evaluated. Our results showed that hMSC-EC secretome enhanced endothelial cell proliferation and wound healing in vivo when compared with hMSC secretome. Five soluble proteins (angiopoietin-1, angiopoietin-2, Factor de crecimiento fibroblástico, Matrix metallopeptidase 9, and Vascular Endothelial Growth Factor) were enriched in hMSC-EC secretome in comparison to hMSC secretome. Thus, the five recombinant proteins were mixed, and their pro-healing property was evaluated in vitro and in vivo. Functional analysis demonstrated that a cocktail of these proteins enhanced the wound healing process similar to hMSC-EC secretome in HFD mice. Overall, our results show that hMSC-EC secretome or a combination of specific proteins enriched in the hMSC-EC secretome enhanced wound healing process under hyperglycemic conditions.

Vascular endothelial growth factor and poor prognosis after ischaemic stroke.

BACKGROUND AND PURPOSE: Systemic inflammation conveys information about ischaemic stroke prognosis. Growth factors with neurotrophic and angiogenesis-regulating properties might provide additional information about sequelae. The prognostic performance of circulating vascular endothelial growth factor (VEGF), placental growth factor, interleukin 6 and C-reactive protein measured after acute ischaemic stroke was evaluated. METHODS: Blood samples were collected from n = 45 patients within 24-48 h of acute ischaemic stroke. The primary outcome was death or moderate to severe disability at 6 months (modified Rankin Scale >2). Logistic regression models were used to determine the area under the receiver operating characteristic curve (AUC). Correlation and principal component analyses were performed to examine interrelationships amongst biomarkers. RESULTS: Vascular endothelial growth factor was elevated in ischaemic stroke patients who died or had moderate to severe disability at six months. Correlation analysis revealed interrelationships between VEGF and HbA1c, triglycerides, erythrocyte sedimentation rate and National Institutes of Health Stroke Scale and Rankin scores, whereas principal component analyses identified VEGF as a major loading factor that discriminated good from poor prognosis. There were no significant differences in AUC using each protein individually to identify patients who had modified Rankin Scale score >2 at 6 months (n = 15/41, AUC 0.61-0.74). However, the AUC increased significantly when combining VEGF with interleukin 6 and C-reactive protein compared to the VEGF-only model (AUC 0.92 vs. 0.67, p = 0.02). CONCLUSION: Circulating VEGF was elevated 24-48 h after acute ischaemic stroke and conveyed prognostic information about moderate to severe disability at 6 months.

NordAqua, a Nordic Center of Excellence to develop an algae-based photosynthetic production platform.

NordAqua is a multidisciplinary Nordic Center of Excellence funded by NordForsk Bioeconomy program (2017-2022). The research center promotes Blue Bioeconomy and endeavours to reform the use of natural resources in a environmentally sustainable way. In this short communication, we summarize particular outcomes of the consortium. The key research progress of NordAqua includes (1) improving of photosynthetisis, (2) developing novel photosynthetic cell factories that function in a "solar-driven direct CO2 capture to target bioproducts" mode, (3) promoting the diversity of Nordic cyanobacteria and algae as an abundant and resilient alternative for less sustainable forest biomass and for innovative production of biochemicals, and (4) improving the bio-based wastewater purification and nutrient recycling technologies to provide new tools for integrative circular economy platforms.

The activity of IKCa and BKCa channels contributes to insulin-mediated NO synthesis and vascular tone regulation in human umbilical vein.

Insulin regulates the l-arginine/nitric oxide (NO) pathway in human umbilical vein endothelial cells (HUVECs), increasing the plasma membrane expression of the l-arginine transporter hCAT-1 and inducing vasodilation in umbilical and placental veins. Placental vascular relaxation induced by insulin is dependent of large conductance calcium-activated potassium channels (BKCa), but the role of KCa channels on l-arginine transport and NO synthesis is still unknown. The aim of this study was to determine the contribution of KCa channels in both insulin-induced l-arginine transport and NO synthesis, and its relationship with placental vascular relaxation. HUVECs, human placental vein endothelial cells (HPVECs) and placental veins were freshly isolated from umbilical cords and placenta from normal pregnancies. Cells or tissue were incubated in absence or presence of insulin and/or tetraethylammonium, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, iberiotoxin or NG-nitro-l-arginine methyl ester. l-Arginine uptake, plasma membrane polarity, NO levels, hCAT-1 expression and placenta vascular reactivity were analyzed. The inhibition of intermediate-conductance KCa (IKCa) and BKCa increases l-arginine uptake, which was related with protein abundance of hCAT-1 in HUVECs. IKCa and BKCa activities contribute to NO-synthesis induced by insulin but are not directly involved in insulin-stimulated l-arginine uptake. Long term incubation (8 h) with insulin increases the plasma membrane hyperpolarization and hCAT-1 expression in HUVECs and HPVECs. Insulin-induced relaxation in placental vasculature was reversed by KCa inhibition. The results show that the activity of IKCa and BKCa channels are relevant for both physiological regulations of NO synthesis and vascular tone regulation in the human placenta, acting as a part of negative feedback mechanism for autoregulation of l-arginine transport in HUVECs.

Deletion of the adenosine A2A receptor increases the survival rate in a mice model of polymicrobial sepsis.

We aim to investigate the role of A2A receptor in peritonitis-related sepsis by injection of a fecal solution (FS) as a model of polymicrobial infection. C57/black J6 wild-type (WT) and A2A-deficient mice (A2AKO) were exposed to sepsis induced by intraperitoneal injection of a FS (FS-induced peritonitis) or instead was injected with saline buffer (Sham). Survival rate and sepsis score were measured up to 48 h. The presence of bacteria in tissue homogenates was analyzed. Telemetry and speckle laser Doppler were used for systemic blood pressure and peripheral blood perfusion analysis, respectively. Histological analysis and identification of active caspase 3 were performed in selected organs, including the liver. The survival rate of A2AKO mice exposed to FS-induced peritonitis was significantly higher, and the sepsis score was lower than their respective WT counterpart. Injection of FS increases (50 to 150 folds) the number of colonies forming units in the liver, kidney, blood, and lung in WT mice, while these effects were significantly attenuated in A2AKO mice exposed to FS-induced peritonitis. A significant reduction in both systolic and diastolic blood pressure, as well as in the peripheral perfusion was observed in WT and A2AKO mice exposed to FS-induced peritonitis. Although, these last effects were significantly attenuated in A2AKO mice. Histological analysis showed a large perivascular infiltration of polymorphonuclear in the liver of WT and A2AKO mice exposed to FS-induced peritonitis, but again, this effect was attenuated in A2AKO mice. Finally, high expression of active caspase 3 was found only in the liver of WT mice exposed to FS-induced peritonitis. The absence of the A2A receptor increases the survival rate in mice exposed to polymicrobial sepsis. This outcome was associated with both hemodynamic compensation and enhanced anti-bacterial response.

Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17ß-Estradiol.

Estrogenic steroids and adenosine A2A receptors promote the wound healing and angiogenesis processes. However, so far, it is unclear whether estrogen may regulate the expression and pro-angiogenic activity of A2A receptors. Using in vivo analyses, we showed that female wild type (WT) mice have a more rapid wound healing process than female or male A2A-deficient mice (A2AKO) mice. We also found that pulmonary endothelial cells (mPEC) isolated from female WT mice showed higher expression of A2A receptor than mPEC from male WT mice. mPEC from female WT mice were more sensitive to A2A-mediated pro-angiogenic response, suggesting an ER and A2A crosstalk, which was confirmed using cells isolated from A2AKO. In those female cells, 17ß-estradiol potentiated A2A-mediated cell proliferation, an effect that was inhibited by selective antagonists of estrogen receptors (ER), ERα, and ERß. Therefore, estrogen regulates the expression and/or pro-angiogenic activity of A2A adenosine receptors, likely involving activation of ERα and ERß receptors. Sexual dimorphism in wound healing observed in the A2AKO mice process reinforces the functional crosstalk between ER and A2A receptors.