Rodrigo Iturriaga

Background: It is not well-known whether cardiovascular alterations elicited by adolescent binge drinking (ABD) are reversible or if they persist following long-term abstinence until adult life. Thus, we studied the long-term impact of ABD on oxidative stress, inflammation and cardiovascular function. Methods: Twenty-four adolescent Sprague-Dawley rats underwent a controlled or ABD-like protocol, (ethanol 3.00 g/kg i.p.) starting at postnatal day 25 (PND25) to PND38, followed by long-term abstinence until PND70 (adulthood). Results: ABD resulted in overt cardiac dysfunction in adult rats. We found a decreased left ventricular compliance as evidenced by a marked reduction in the early-to-late mitral valve blood flow (E/A: 1.23 ± 0.14 vs. 1.51 ± 0.09, control vs. ABD, p < 0.05). Importantly, cardiac dysfunction was closely linked to adverse cardiac remodeling and fibrosis in ABD animals compared to control animals. Furthermore, we found that ABD resulted in a significant increase in cardiac arrhythmogenesis. Indeed, ABD rats showed a 2-fold increase in the incidence of cardiac arrhythmias compared to control rats (53.6 ± 12.7 vs. 21.7 ± 5.7 events/h, Control vs. ABD, p < 0.05). Finally, we found that cardiac functional impairments were accompanied by increases in cardiac tissue oxidative stress and upregulated levels of pro-inflammatory cytokines (i.e., IL-1β and TNF-α). Conclusions: Present results show that ABD drives long-lasting cardiac dysfunction that persists during early adulthood. Oxidative stress and inflammation may contribute to long-term cardiovascular alterations induced by ABD.

Human acclimatization to both high-altitude and microgravity is crucial for terrestrial and space exploration. Although these extreme environments elicit several similar physiological responses, including autonomic imbalance, metabolic stress, and reduced exercise capacity, the underlying central mechanisms remain unclear. However, these effects appear to be linked to chemoreflex control. This review summarizes current evidence and proposed potential similarities and bioconvergent mechanisms underlying human responses to both terrestrial and extraterrestrial environments.

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.

This study reveals that carotid body (CB) chemoreceptors contribute to muscle dysfunction induced by simulated microgravity. In rats, hind-limb suspension increased hypoxic ventilatory drive and impaired muscle strength, mass, and V̇o _2peak . Inhibiting CB chemosensory activity significantly attenuated these effects. These findings identify a novel physiological role for CBs in mediating microgravity-induced muscle decline, suggesting that the CB chemoreflex may be a potential target for preserving physical performance during spaceflight or similar conditions.

Cardiorespiratory responses to physical exercise are expected to meet the organism's metabolic demands. As carotid body (CB) glomus cells have been proposed as metabolic sensors, we sought to determine their contribution to peak oxygen uptake () during exercise in rats. Adult male Wistar Kyoto rats underwent bilateral co‐injection of two adeno‐associated viruses (AAVs) at the CB bifurcation (AVV‐TH‐Cre‐SV40 and AVV‐hSyn‐DREADD(Gi)‐mCherry). Clozapine‐ N ‐oxide (1 mg/kg, i.p. ) was administered to activate the inhibitory DREADD‐Gi receptor and suppress CB chemosensory activity. Three weeks after AVV infection we evaluated ventilatory and CB chemosensory responses to sodium cyanide (NaCN), the hypobaric‐hypoxic ventilatory response (HHVR), lactate‐dependent ventilatory response, arterial blood pressure, exercise performance and . Chemogenetic inhibition of CB glomus cells reduced resting oxygen consumption and ventilatory responses to lactate. In anaesthetized rats acute chemogenetic inhibition of glomus cells markedly diminished the CB chemosensory and ventilatory responses elicited by NaCN, as well as lactate‐dependent hyperventilation after CB resection. Similarly HHVR was markedly reduced in non‐anaesthetized animals. Notably chemogenetic inhibition of CB glomus cells significantly reduced without altering the time required to reach it. These findings support a novel role for CB glomus cells as metabolic sensors that influence during maximal physical exertion, independent of overall exercise performance. image Key points: Carotid body (CB) glomus cells may function as sensors of metabolic activity through the release of lactate from muscle and its accumulation during physical exertion. CB type I chemoreceptor cells are necessary and play a crucial role in sensing metabolism at rest and during exertion. The CB acts as a metabolic sensor that triggers metabolism during physical exertion, mediating the increment of peak O ₂ uptake during exertion, without affecting exercise performance.

The carotid body (CB) senses arterial PO₂, PCO₂, and pH levels, eliciting reflex responses to maintain cardiorespiratory homeostasis. Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea, elicits autonomic and cardiorespiratory alterations that are attributed to an enhanced CB chemosensory responsiveness to hypoxia, which in turn activates neurons and glial cells in the nucleus of the tractus solitarius (NTS). Although the CB contribution to the CIH-induced pathological alterations is well-known, the underlying mechanisms are not fully understood. A growing body of new evidence suggests a crucial role for ROS in acute CB oxygen sensing, as well as in the potentiation of chemosensory discharge and the activation of the central chemoreflex pathway in CIH. Indeed, it has been proposed that acute hypoxia disrupts mitochondrial electron transport, increasing ROS and NADH in the chemoreceptor cells, which inhibit voltage-gated K⁺ channels, producing cell depolarization, Ca²⁺ entry, and release of excitatory transmitters. In addition, new evidence supports that the enhanced CB afferent discharge contributes to persistent CIH-induced cardiorespiratory alterations, likely triggering neuroinflammation in the NTS. Thus, in this review, we will examine the experimental evidence that supports the involvement of ROS in the acute O₂ sensing process, and their role in the enhanced CB chemosensory discharges, the glial-related inflammation in the NTS, and the cardiorespiratory alterations induced by CIH.

Chronic intermittent hypoxia (CIH), a feature of obstructive sleep apnea, causes cardiorespiratory alterations (i.e. hypertension) linked to oxidative stress, inflammation, and sympathoexcitation. In the present study, we highlight the role of enhanced carotid body (CB) chemosensory afferent discharges to the nucleus of the solitary tract (NTS) in long-term CIH-induced cardiorespiratory disorders. Indeed, we provide evidence that supports the notion that increased CB afferent activity contributes to persistent CIH-induced hypertension, likely triggering neuroinflammation in the NTS.

Obstructive sleep apnoea (OSA), characterized by chronic intermittent hypoxia (CIH), is considered to be an independent risk for hypertension. The pathological cardiorespiratory consequences of OSA have been attributed to systemic oxidative stress, inflammation and sympathetic overflow induced by CIH, but an emerging body of evidence indicates that a nitro‐oxidative and pro‐inflammatory milieu within the carotid body (CB) is involved in the potentiation of CB chemosensory responses to hypoxia, which contribute to enhance the sympathetic activity. Accordingly, autonomic and cardiovascular alterations induced by CIH are critically dependent on an abnormally heightened CB chemosensory input to the nucleus of tractus solitarius (NTS), where second‐order neurons project onto the rostral ventrolateral medulla (RVLM), activating pre‐sympathetic neurons that control pre‐ganglionic sympathetic neurons. CIH produces oxidative stress and neuroinflammation in the NTS and RVLM, which may contribute to the long‐term irreversibility of the CIH‐induced alterations. This brief review is mainly focused on the contribution of nitro‐oxidative stress and pro‐inflammatory molecules on the hyperactivation of the hypoxic chemoreflex pathway including the CB and the brainstem centres, and whether the persistence of autonomic and cardiorespiratory alterations may depend on the glial‐related neuroinflammation induced by the enhanced CB chemosensory afferent input. image