Introduction: Gestational hypoxia (GH) increases the risk of cardiovascular diseases by inducing oxidative stress and vascular dysfunction. This study investigates whether prenatal melatonin can mitigate these effects in guinea pigs. Methods: Pregnant guinea pigs were exposed to normoxia or hypoxia and treated with melatonin (1 mg/kg/day). Echocardiography, vascular reactivity, and molecular assays were used to assess cardiovascular structure, function, and redox balance in neonates. Results: GH reduced neonatal birth weight and altered left ventricular (LV) development, resulting in increased LV systolic function and aortic blood flow velocity. Melatonin treatment reversed these effects, restoring endothelial-dependent vasodilation and decreasing oxidative stress in the LV and thoracic aorta. Catalase antioxidant enzyme activity was elevated in melatonin-treated hypoxic neonates. Unexpectedly, melatonin treatment altered cardiac structure in normoxic pregnancies, increasing LV length and decreasing LV myocardial nuclei density. Conclusions: Prenatal melatonin partially modulates GH-induced endothelial dysfunction and oxidative stress, offering potential therapeutic value. However, its effects under normoxic conditions deserve caution, emphasizing the need for targeted use only in pregnancies with evident hypoxic and oxidative stress conditions.

Chronic exposure to hypobaric hypoxia (HH) during gestation, typical of high-altitude environments (>= 2500 m), is known to affect fetal development; however, its long-term vascular consequences remain poorly understood. This study evaluated the biomechanical, functional, and morphostructural effects of gestational HH on the descending thoracic aorta (DTA) of adult guinea pigs. Pregnant animals were exposed to normoxia (group N) or HH (group H) during gestation, and offspring were maintained under normoxic conditions until one year of age. Mechanical behavior was characterized through tensile, ring-opening, and axial pre-stretching tests, while ex-vivo vasomotor function was assessed using wire myography and histological analysis. HH offspring showed increased material stiffness and residual strain, reduced axial physiological strain, diminished vasodilation, and enhanced vasocon striction. Histology revealed thicker walls, larger luminal radii, elevated collagen and elastin content, and fewer

Oxidative stress is an early and important feature of Alzheimer’s disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress. Metformin modulates the Nrf2/KEAP1 pathway and enhances antioxidant defenses in hippocampal neurons. Metformin increases the protein levels and activity of key antioxidant enzymes, including SOD, CAT, and GPx. Metformin attenuates AβOs-induced lipid peroxidation in primary hippocampal cultures.

BACKGROUND:Melatonin, an anti-inflammatory-antioxidant neurohormone, is considered for the treatment of neonatal hypoxic-ischemic-encephalopathy. However, its effects on the developing cardiopulmonary system are poorly defined. We investigated how postnatal melatonin administration alters cardiopulmonary structure, function, and responses to acute hypoxia in newborn lambs. METHODS:Twenty term-newborn lambs received melatonin (0.25 mg kg-1, n = 9) or vehicle (n = 11) daily from birth to day 5. Echocardiography was performed in 15 lambs (7 melatonin; 8 vehicle; day 5). On day-6, five lambs per group underwent 30-min of hypoxia followed by euthanasia. Cardiovascular physiology, morphology, cardiomyocyte size, gene expression, and lung morphology were analyzed. RESULTS:At normoxia, melatonin-treated lambs showed normal systemic function but altered cardiac hemodynamics and morphology compared to vehicle-treated lambs. During hypoxia, melatonin-treated lambs exhibited a blunted sympatho-circulatory response, with no increase in mean pulmonary arterial pressure and cardiac output. Additionally, heart weight and cardiomyocyte cross-sectional area were reduced, and pulmonary arteriole density increased. Gene expressions showed reduced cardiomyocyte markers in the right ventricle and left atrium but increased protective gene expression in the left ventricle. CONCLUSIONS:Postnatal melatonin triggers notable cardiopulmonary remodeling, reducing physiological flexibility to respond to hypoxic stress, highlighting the need to weigh its therapeutic benefits against potential cardiovascular risks. IMPACT:This study examined the effects of melatonin treatment on the cardiopulmonary system during the early neonatal period in lambs, when endogenous melatonin production is limited. Melatonin induces significant cardiopulmonary remodeling in newborn lambs, characterized by reduced heart weight and ventricular cardiomyocyte size, increased pulmonary arteriole density, and altered cardiac chamber gene expression. While these changes maintain normal cardiovascular function at normoxic-baseline, they compromise the system's ability to respond to acute hypoxia, revealing a diminished physiological flexibility. The study highlights the need to balance melatonin's therapeutic promise with caution regarding its potential developmental consequences on the cardiopulmonary system.

Hypoxia plays a critical role in regulating vascular function, with endothelial mechanosensitive proteins, such as the piezo-type mechanosensitive ion channel component 1 (Piezo1), emerging as key players in maintaining vascular homeostasis. Piezo1 is essential for nitric oxide-mediated vasodilation and vascular tone regulation. However, the impact of hypoxia on endothelial Piezo1 expression and function remains poorly understood. The present study investigated the regulation of Piezo1 and mechanosensitive-related genes (MRGs) during hypoxic development and their role in fetal growth restriction (FGR). Using publicly available datasets, we identified distinct transcriptional profiles in placental endothelial cells from human FGR pregnancies and human umbilical vein endothelial cells (HUVEC) exposed to hypoxia. Functional enrichment analysis revealed significant changes in pathways related to PI3K-Akt, MAPK, and VEGF signaling and responses to mechanical stimuli. Hypoxia-related transcription factors, particularly HIF-1α and HIF-1β, were enriched in the promoter regions of differentially expressed MRGs, including Piezo1, suggesting a conserved regulatory mechanism. In vitro experiments confirmed hypoxia-induced down-regulation of Piezo1 in HUVEC, while ex vivo studies using a chicken embryo model demonstrated impaired Piezo1-mediated vasodilation following hypoxic development. Combined, these findings highlight the critical role of hypoxia in modulating endothelial Piezo1 expression and function, providing mechanistic insights into vascular dysfunction associated with FGR. The present study provides evidence for the potential to target Piezo1 and HIF-1α signaling as therapeutic strategies to improve vascular outcomes in offspring of pregnancies complicated by hypoxia and FGR.

High-altitude workers in the Los Andes Mountains, known as “the Chilean miner model,” are exposed to chronic intermittent hypobaric hypoxia (CIHH). This intermittent condition differs from other models of chronic hypoxia, mainly due to the hypoxic pattern and the cardiovascular and pulmonary effects. There are reports of cardiopulmonary dysfunction and remodeling in human and animal models. However, research on some mechanisms of vascular function and the consequences of lung remodeling induced by CIHH is still lacking. Therefore, this study aims to characterize the effects of CIHH exposure on lung structure and redox status in a rat model of the Chilean miner, involving intermittent exposure to chronic cycles of normoxia/hypobaric hypoxia (96 h/96 h) in an experimental hypoxic chamber. Our results demonstrate that CIHH acts as a primary driver of pulmonary vascular remodeling by significantly increasing the medial wall thickness of small pulmonary arteries (<100 μm) and promoting a shift toward a more muscularized phenotype in previously non-muscularized vessels. Structurally, this was characterized by a marked reduction in alveolar space and a significant increase in the thickness of the alveolar-capillary barrier, suggesting impaired gas exchange capacity. These structural changes were strongly associated with a pro-oxidant state, evidenced by increased lipid peroxidation (malondialdehyde levels) and a concomitant reduction in antioxidant enzyme activities, such as superoxide dismutase (SOD) and catalase (CAT), in lung tissue. In conclusion, the CIHH model effectively replicates the complex interplay between chronic oxidative damage and structural lung remodeling, identifying the thickening of the arterial medial wall and alveolar septa as key pathological features of probably CIHH-induced pulmonary hypertension.

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus’s failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia. In this regard, this study aims to describe the effect of gestational hypoxia on redox balance and apoptosis cell death mechanisms in the prefrontal cortex of guinea pigs. Ten Guinea pig (Cavia porcellus) pregnant dams were utilized in this study; five gestated in normoxia (Nx; three newborn males, and two females) and five gestated under chronic hypobaric hypoxia (Hx; two newborn males, and three females). We monitored the pregnancies by ultrasound examinations from gestational days 20 to 65 (term ~ 70). At birth, pups were euthanized, and the fetal brain was collected for cellular redox measurement, mitochondrial enzyme expression, and apoptosis assay. Gestation under hypoxia induced an imbalance in the expression of anti- and pro-oxidant enzymes, resulting in increased oxidative stress. Additionally, a decrease in cytochrome I and III expression and neuronal density in the neonatal prefrontal cortex was observed. Finally, DNA fragmentation was increased by the TUNEL assay in the brain tissue of newborns gestated under chronic hypoxia. Our findings demonstrate the association of gestational hypoxia with oxidative stress and neuronal death in newborns, which may predispose to neuronal dysfunction in adulthood.

Cardiopulmonary bypass (CPB) can lead to cardiac damage due to oxidative stress (OS) and inflammation in heart failure (HF). We tested the hypothesis that preoperative HF patients with reduced ejection fraction (HFrEF) subjected to CBP have higher levels of OS and NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) in heart and plasma and in those that develop postoperative AF (pAF) as a clinical outcome. HF was categorized for preoperative left ventricular EF: preserved (HFpEF > 50%, n = 27) and reduced EF (HFrEF ≤ 40%, n = 25). Samples of atrial tissue, pericardial fluid, and plasma were collected at surgery to assess NLRP3 expression; 3-nitrotyrosine (3-NT), thiobarbituric acid reaction (TBARS), and nuclear factor erythroid 2-related factor 2 (Nrf2) in atrial tissue; NLRP3, IL-1β, and IL-18 expression in pericardial fluid; and antioxidant capacity, 8-isoprostanes, and malondialdehyde (MDA) in plasma. Reactive oxygen species, 3-NT, and NLRP3 in atrial tissue were determined by immunohistochemistry in a subset of pAF patients. Plasma and atrial tissue 3-NT and MDA were higher in HFrEF compared with HFpEF. Lipid peroxidation products were higher in both plasma and atrial tissue in pAF (n = 29), compared to sinus rhythm (SR) (n = 23). In HFrEF patients, the values of tissue ROS, 3-NT, and NLRP3 were higher than in HFpEF patients. In addition, the expression levels of NLRP3, IL-1β, and IL-18 were higher in atrial tissue and pericardial fluid in HFrEF. Patients with preoperative HFrEF showed higher OS in plasma and the expression of NLRP3, ROS, and 3-NT in atrial tissue biopsies and pericardial fluid. This finding suggests a potential pharmacologic therapy for pAF and clinical complications due to CPB.

Pulmonary arterial hypertension (PAH) Group 1 from the World Health Organization (WHO) is a rare, severe chronic, and progressive condition. Patients with PAH have increased oxidative stress (OS) and diminished antioxidant capacity. Melatonin is a potent antioxidant hormone with reported benefits in PAH animal models. We aimed to evaluate the functional, hemodynamic, and antioxidant response to a 6-month melatonin therapy in PAH Group 1 patients. Clinical evaluation was done at baseline (BT), as well as at 3 (T3) and 6 (T6) months of melatonin treatment in stable PAH Group 1 (WHO) patients. The principal endpoint was change in walking distance (WD) in the 6-min walking test (6MWT). Secondary endpoints were functional class (FC), quality of life (QoL), performance of right ventricle (RV), and plasma antioxidant capacity. This study included 19 patients. They were mainly women in WHO FC II and III. A significant improvement was noticed in perception of dyspnea, palpitations, and fatigue in concordance with the QoL improvement in the physical domain after 6 months of melatonin. This was represented by a significant fall in the total score of the PAH-SYMPACT questionnaire. In addition, the baseline heart rate was lower at the T6 follow-up. No significant changes were seen in the echocardiographic variables. However, the biochemical analysis showed significative increases in plasma total antioxidant (2.94 ± 0.13 vs. 8.41 ± 0.19) and ferric reducing (191 ± 12 vs. 256 ± 17) capacities. Overall, oral melatonin treatment improved the plasma antioxidant capacity and the QoL in this pilot study.

BACKGROUND:Fetal growth restriction (FGR) causes an adaptive redistribution of the cardiac output towards sustained cerebral vasodilation. However, the consequences of FGR and cerebral vasodilatation due to fetal hypoxia on the blood-brain barrier (BBB) are still poorly studied. This study assesses BBB permeability in the neonatal cortex of pups gestated under intrauterine hypobaric hypoxia. METHODS:15 Guinea pig (Cavia porcellus) newborns were used in this study; 8 were gestated in normoxia (Nx), and 7 were gestated under chronic hypobaric hypoxia (Hx). Fetal examinations by ultrasound were assessed. At birth, pups were euthanized, and the cerebral cortex was collected to determine gene and protein expression. The permeability was quantified by immunolocalization of perivascular albumin in the prefrontal cortex BBB. RESULT:The brain-sparing phenotype was associated with increased medial cerebral artery vasodilation during gestation and carotid endothelial vasodilation at birth. Additionally, gestational hypoxia decreased the protein levels of claudin-5 and claudin-12 in the neonatal cortex. Finally, albumin-immunopositive areas significantly increased in the brain parenchyma in the Hx neonatal cortex. CONCLUSION:Our findings demonstrate that gestational hypoxia is associated with changes in the expression of genes and proteins related to the paracellular permeability of the BBB, which appears relevant to normal neurodevelopmental processes in perinatal life. IMPACT:Gestational hypoxia generated a redistribution of flow (brain-sparing effects) associated with an increase in the cerebroplacental index and a growth restriction at birth using guinea pigs as an FGR model. The brain-sparing phenotype is associated with a decrease in the expression of claudins in the cerebral vasculature and increased BBB permeability in newborns gestated in hypobaric hypoxia. The observed permeability of the BBB in the neonatal cortex resembles the permeability phenotypes of postnatal hypoxia models, such as those of cerebral infarction or neonatal ischemic encephalopathy.

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus's failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia. In this regard, this study aims to describe the effect of gestational hypoxia on redox balance and apoptosis cell death mechanisms in the prefrontal cortex of guinea pigs. Ten Guinea pig (Cavia porcellus) pregnant dams were utilized in this study; 5 gestated in normoxia (Nx), and 5 gestated under chronic hypobaric hypoxia (Hx). We monitored the pregnancy by ultrasound examinations from gestational days 20 to 65 (term ~70). At birth, pups were euthanized, and the fetal brain was collected for cellular redox measurement, mitochondrial enzyme expression, and apoptosis assay. Gestation under hypoxia induced an imbalance in the expression of anti- and prooxidant enzymes, resulting in increased oxidative stress. Additionally, a decrease in cytochrome I and III expression and neuronal density in the neonatal prefrontal cortex was observed. Finally, DNA fragmentation was increased by Tunel assay in the brain tissue of newborns gestated under chronic hypoxia. Our findings demonstrate the association of gestational hypoxia with oxidative stress and neuronal death in newborns, which may predispose to neuronal dysfunction in adulthood.

Background: Gestational hypoxia (GH) has been implicated in the developmental programming of cardiovascular diseases (CVDs) in the offspring, with most studies focusing on males, conversely, the effects on female cardiovascular health remain understudied. We aimed to investigate the impact of GH on the cardiovascular system of female guinea pig offspring from the early postnatal period to adulthood. Methods: Pregnant guinea pigs were subjected to normoxic or hypoxic conditions from gestational day 30 until delivery (similar to 70 days). Female offspring were monitored with biometric parameters and peripheral vascular function (ultrasound) from birth to one year old. In addition, we assessed cardiovascular structure, oxidative stress, inflammatory state (IHC, qPCR, and immunoblot assays), and thoracic aorta reactivity (wire-myography) at one year of age. Key findings: GH increased heart rate and peripheral pulsatility index. At one year old, GH-exposed females exhibited cardiac remodeling, characterized by increased left ventricular luminal area and coronary artery muscle occupation. Furthermore, GH increased aortic vascular wall, intima-media thickness and contractile capacity. This was accompanied by reduced endothelium-dependent vasodilation and enhanced oxidative stress. Additionally, GH increased collagen deposition and oxidative stress in the right ventricle, accompanied by reduced antioxidant enzymes expression and reduced inflammatory mediator levels. Significance: GH exerts long-lasting effects on the cardiovascular health of female guinea pig offspring, contributing to cardiac remodeling, vascular dysfunction, oxidative stress, and inflammatory changes. These findings highlight the importance of GH as a risk factor for developing CVDs in female offspring and emphasize the need for sex-specific interventions to mitigate adverse long-term gestational effects.

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.

Aims: Chronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 x 4 or 7 x 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x lowaltitude (760 m) working shifts.Main methods: We analyzed in vivo cardiac function through echocardiography, ex vivo vascular reactivity by wire myography, and in vitro cardiac morphology by histology and protein expression and immunolocalization by molecular biology and immunohistochemistry techniques in 12 rats, 6 exposed to CIHH in the hypoxic chamber, and respective normobaric normoxic controls (n = 6).Key findings: CIHH induced cardiac dysfunction with left and right ventricle remodeling, associated with an increased collagen content in the right ventricle. In addition, CIHH increased HIF-1 & alpha; levels in both ventricles. These changes are associated with decreased antioxidant capacity in cardiac tissue. Conversely, CIHH decreased contractile capacity with a marked decreased in nitric oxide-dependent vasodilation in both, carotid and femoral arteries. Significance: These data suggest that CIHH induces cardiac and vascular dysfunction by ventricular remodeling and impaired vascular vasodilator function. Our findings highlight the impact of CIHH in cardiovascular function and the importance of a periodic cardiovascular evaluation in high-altitude workers.

Neonatal encephalopathy (NE) is a pathological condition that describes a neurocognitive malfunction in the newborn that arises from fetal, peripartum, or intrapartum events of multifactorial nature, having a poor prognosis and accounting for an incidence of 5-8 per 1000 live births. Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most studied paradigms of NE, caused by a scarce cerebral perfusion and oxygen supply during perinatal life. The cerebral hypoxic-ischemic insult promotes a loss of permeability of the blood-brain barrier (BBB), an essential structural intermediary of blood-brain communication. This permeability disruption is associated with an increase in inflammatory cytokines, an increase of adhesion molecules, and oxidative stress which disturb the tight junction (TJ) performance and enable transcytosis and paracellular leakage, ultimately leading to death from brain cells. In this context, TJs proteins are essential to preserving the barrier mechanical stability and signaling that modulates the brain-blood vessel multicellular domains, known as neurovascular units (NVU). Recent studies have proposed different strategies with neuroprotective effects that allow for maintaining or restoring the integrity and permeability of the BBB. This review identifies and discusses regulator mechanisms and novel aspects of TJs in the BBB disruption induced by cerebral hypoxic insults during the perinatal period, evaluating potential pharmacological strategies to safeguard BBB integrity.

PIEZO1 is a mechanosensitive cation channel implicated in shear stress-mediated endothelial-dependent vasorelaxation. Since altered shear stress patterns induce a pro-inflammatory endothelial environment, we analyzed transcriptional profiles of human endothelial cells to determine the effect of altered shear stress patterns and subsequent prooxidant and inflammatory conditions on PIEZO1 and mechanosensitive-related genes (MRG). In silico analyses were validated in vitro by assessing PIEZO1 transcript levels in both the umbilical artery (HUAEC) and vein (HUVEC) endothelium. Transcriptional profiling showed that PIEZO1 and some MRG associated with the inflammatory response were upregulated in response to high (15 dyn/cm2) and extremely high shear stress (30 dyn/cm2) in HUVEC. Changes in PIEZO1 and inflammatory MRG were paralleled by p65 but not KLF or YAP1 transcription factors. Similarly, PIEZO1 transcript levels were upregulated by TNF-alpha (TNF-α) in diverse endothelial cell types, and pre-treatment with agents that prevent p65 translocation to the nucleus abolished PIEZO1 induction. ChIP-seq analysis revealed that p65 bonded to the PIEZO1 promoter region, an effect increased by the stimulation with TNF-α. Altogether this data showed that NF-kappa B activation via p65 signaling regulates PIEZO1 expression, providing a new molecular link for prooxidant and inflammatory responses and mechanosensitive pathways in the endothelium.