Carotid Body Research Articles

SubSol-HIe is an AMPK-dependent hypoxia-responsive subnucleus of the nucleus tractus solitarius that coordinates the hypoxic ventilatory response and protects against apnoea in mice

Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.

Bioelectronic modulation of carotid sinus nerve to treat type 2 diabetes: current knowledge and future perspectives.

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future.

Novel insights into the classification of Shamblin III carotid body tumors from a neurosurgical perspective

Background and purposeThe classic Shamblin system fails to provide valuable guidance in many Shamblin’s III carotid body tumors (III-CBTs) due to the variable forms of carotid arteries and the complex anatomic relationships in parapharyngeal space. We proposed a modified classification to separately divide III-CBTs into different subgroups on the basis of arterial relevant features and anatomical relevant features.Materials and methodsFrom 2020 to 2023, a total of 129 III-CBTs at a single institution were retrospectively analyzed. All cases were independently classified as arterial-relevant and anatomical-relevant subgroups. The pre-, peri- and postoperative data were summarized and compared accordingly.ResultsAmong the 129 cases, 69 cases were identified as “Classical type”, 23 cases as “Medial type”, 27 cases as “Lateral type” and 10 cases as “Enveloped type” according to arterial morphologies. Besides, 76 cases were identified as “Common type”, 15 cases as “Pharynx- invasion type”, 18 cases as “Skull base-invasion type” and 20 cases as “Mixed type” according to anatomical relationships. “Enveloped type” of tumors in arterial-relevant classification and “Mixed type” of tumors in anatomical-relevant classification are the most challenging cases for surgeons with the lowest resection rate, highest incidence of carotid arteries injury and postoperative stroke.ConclusionThe modified classifications provide comprehensive understanding of different III-CBTs which are applicable for individualized treatment in clinical practice.

Fifteen Years of Experience with Surgical Management of Bilateral Non-familial Carotid Body Tumors

Bilateral carotid body tumors (CBTs) clinical manifestation is infrequent. We conducted this work to describe our experience in the surgical treatment of bilateral CBT and to analyze our results. A retrospective, observational study. We analyzed the totality of bilateral CBT resections that had been performed in our institution from January 2008 to September 2023. Data was obtained from medical records and anonymized, ethics approval was obtained from our institution committee. As the number of observations was less than those required by the central limit theorem our sample was considered nonparametric. Statistical analysis was performed on Stata17. We evaluated 16 patients with a total of 32 CBT; surgical resection was performed in 28 cases (87.50%). Median age of the patients was 60years (interquartile range [IQR] 46-64). Regarding the Shamblin classification, 9 CBTs (32.14%) were classified as Shamblin I, 11 (39.29%) as Shamblin II, and 8 (28.57%) as Shamblin III. The median Distance to the Base of the Skull (DTBOS) was 3.5cm (IQR 2.7-5.1), and the median tumor volume was 11.25cc (IQR 3.4-18.7). The median bleeding volume was 300ml (IQR 200-500), and the median surgical time was 190min (IQR 145-240). All surgeries were performed using the Retrocarotid Dissection technique. We documented 9 (32.14%) cases of nerve injuries, all of which were transitory. In the median regression a statistically significant association was found between DTBOS, Shamblin classification and tumor volume with intraoperative bleeding and length of stay. Surgical treatment remains safe and should be considered the gold standard for accurate histologic diagnosis. DTBOS and tumor volume, in addition to Shamblin classification, must be considered in preoperative planning to predict bleeding and hospital stay.

Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial.

The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%. In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.

Oxygen is an essential gasotransmitter directly sensed via protein gasoreceptors.

The current restrictive criteria for gasotransmitters exclude oxygen (O2) as a gasotransmitter in vertebrates. In this manuscript, I propose a revision of gasotransmitter criteria to include O2 per se as a signaling molecule and 'essential gasotransmitter' for vertebrates. This revision would enable us to search for protein-based O2-binding sensors (gasoreceptors) in all cells in the brain or other tissues rather than specialized tissues such as the carotid body or gills. If microorganisms have protein-based O2-binding sensors or gasoreceptors such as DosP or FixL or FNR with diverse signaling domains, then eukaryotic cells must also have O2-binding sensors or gasoreceptors. Just as there are protein-based receptor(s) for nitric oxide (GUCY1A, GUCY1B, CLOCK, NR1D2) in cells of diverse tissues, it is reasonable to consider that there are protein-based receptors for O2 in cells of diverse tissues as well. In mammals, O2 must be acting as a gasotransmitter or gaseous signaling molecule via protein-based gasoreceptors such as androglobin that very likely mediate acute sensing of O2. Accepting O2 as an essential gasotransmitter will enable us to search for gasoreceptors not only for O2 but also for other nonessential gasotransmitters such as hydrogen sulfide, ammonia, methane, and ethylene. It will also allow us to investigate the role of environment-derived metal ions in acute gas (or solute) sensing within and between organisms. Finally, accepting O2 per se as a signaling molecule acting via gasoreceptors will open up the field of gasocrinology.

Carotid Body Tumor: 30-Day Outcomes After Surgical Intervention

Carotid Body Tumor: 30-Day Outcomes After Surgical Intervention

Metabolic Crossroads: Unveiling the Complex Interactions between Obstructive Sleep Apnoea and Metabolic Syndrome.

Obstructive sleep apnoea (OSA) and components of metabolic syndrome (MetS) are inextricably connected. Considering the increasing burden of MetS and OSA, in the present review, we aimed to collate and summarise the potential pathophysiological mechanisms linking these pathologies. In short, obesity appears to promote OSA development via multiple pathways, some of which are not directly related to mass but rather to metabolic complications of obesity. Simultaneously, OSA promotes weight gain through central mechanisms. On the other hand, diabetes mellitus contributes to OSA pathophysiology mainly through effects on peripheral nerves and carotid body desensitization, while intermittent hypoxia and sleep fragmentation are the principal culprits in OSA-mediated diabetes. Apart from a bidirectional pathophysiological relationship, obesity and diabetes mellitus together additively increase cardiovascular risk in OSA patients. Additionally, the emergence of new drugs targeting obesity and unequivocal results of the available studies underscore the need for further exploration of the mechanisms linking MetS and OSA, all with the aim of improving outcomes in these patients.

Transcriptomic Analysis of Postnatal Rat Carotid Body Development.

The carotid body (CB), located bilaterally at the carotid artery bifurcations, is the primary sensory organ for monitoring arterial blood O2 levels. Carotid bodies are immature at birth, exhibiting low sensitivity to hypoxia, and become more sensitive with maturation during the first few weeks of neonatal life. To understand the molecular basis for the postnatal developmental hypoxic responses of CB, we isolated CBs from 5-day and 21-day-old Sprague-Dawley rats and performed RNA sequencing, which allows comprehensive analysis of gene expression. Differentially expressed genes (DEGs) were generated using Edge R, while functional enrichment analysis was performed using gene-set enrichment analysis (GSEA). Analysis of RNA-Seq data showed 2604 DEGs of the total 12,696 genes shared between neonates and adults. Of the 2604 DEGs, 924 genes were upregulated, and 1680 genes were downregulated. Further analysis showed that genes related to oxidative phosphorylation (Ox/phos) and hypoxia-signaling pathways were significantly upregulated in neonatal CBs compared to adult CBs, suggesting a possible link to differential developmental hypoxic responses seen in CB. Genes related to cytokine signaling (INFγ and TNFα) and transcription factors (CREB and NFΚB) mediated pathways were enriched in adult CBs, suggesting that expression of these pathways may be linked to developmental regulation. The RNA-Seq results were verified by analyzing mRNA changes in selected genes by qRT-PCR. Our results of enrichment analysis of biological pathways offer valuable insight into CB hypoxic sensing responses related to the development process.

Immunohistochemical localization of P2Y12 purinoceptors in the rat carotid body

The present study investigated the localization of the adenosine 5′-diphosphate (ADP)-selective P2Y12 purinoceptors in the rat carotid body using multilabeling immunofluorescence. Punctate immunoreactive products for P2Y12 were distributed in chemoreceptive type I cells immunoreactive to vesicular nucleotide transporter (VNUT) or dopamine beta-hydroxylase, but not in S100B-immunoreactive glial-like type II cells. P2Y12 immunoreactivity was localized in cell clusters containing VNUT-immunoreactive type I cells surrounded by the perinuclear cytoplasm and cytoplasmic processes of type II cells immunoreactive for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and NTPDase3, which hydrolyze extracellular nucleotide tri- and/or di-phosphates. In ATP bioluminescence assays using carotid bodies, the degradation of extracellular ATP was attenuated in the presence of the selective NTPDases inhibitor ARL67156, suggesting ATP-degrading activity by NTPDases in the tissue. These results suggest that ATP released from type I cells is degraded into ADP and adenosine 5′-monophosphate by NTPDases expressed in type II cells, and that ADP modulates type I cells via P2Y12 purinoceptors.

Paraneoplastic Limbic Encephalitis From a Carotid Body Paraganglioma Presenting as Persistent and Worsening Confusion

Background: Paraneoplastic Syndromes (PNS) are rare conditions in which patients experience a variety of symptoms from altered immune systems due to underlying malignancy. Paraneoplastic Limbic Encephalitis (PLE) is a subtype of PNS in which autoantibodies to cancer cells cross-react with cells in the central nervous system, particularly in the medial temporal lobe. Here we present a 38-year-old, previously normal male who presented with persistent and worsening confusion and was diagnosed with a very rare PLE secondary to a carotid body paraganglioma. Case: A 38-year-old male with medical history of hypertension and polysubstance abuse was admitted initially for confusion, arm weakness, and memory loss. He denied having headache, fever, chills, or neck stiffness. Further history obtained from family revealed he was previously cognitively intact. Imaging was consistent with carotid body paraganglioma and limbic encephalitis. A 5-day course of high dose steroids and plasmapheresis was initiated. Plasmapheresis was performed every other day for 5 treatments with marked improvement in mental and renal function at the time of the third treatment. Biopsies obtained were consistent with carotid body paraganglioma and surrounding lymphadenopathy was negative for disease. Embolization was performed with subsequent excision of the tumor and eventual resolution of symptoms. Conclusion: This is to our knowledge the first documented case of paraneoplastic limbic encephalitis associated with a carotid body paraganglioma. Our patient had improved following resection of the underlying paraganglioma and experienced short-term improvement with high-dose steroids and plasmapheresi

A Global Bibliometric Analysis of the Top 100 Most Cited Articles on Carotid Body Tumors.

The carotid body, situated at the common carotid artery bifurcation, comprises specialized glomus cells responsible for sensing blood oxygen, carbon dioxide, pH, and temperature changes, crucial for regulating breathing and maintaining oxygen homeostasis. Carotid body tumors (CBTs), arising from these cells, are rare, representing only 0.5% of head and neck tumors, often presenting as benign, slow-growing, vascularized masses. In February 2023, this bibliometric analysis was conducted, which involved screening 1733 articles from the Web of Science database. The screening process was based on citation count, and articles were selected for inclusion based on specific criteria that focused on CBTs located within the carotid bifurcation. Rigorous selection involved independent screening and data extraction by four authors. The top 100 articles, published between 1948 and 2019, totaled 6623 citations and were authored by 98 unique first authors from 22 countries and 77 institutions, spanning 42 journals. Treatment articles were the predominant category, comprising 49% of the literature. This analysis offers insights into publication trends, identifies literature gaps, and outlines areas of research focus, providing a valuable resource to guide future studies on CBTs.

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice.

The Olfr78 gene encodes a G-protein-coupled olfactory receptor that is expressed in several ectopic sites. Olfr78 is one of the most abundant mRNA species in carotid body (CB) glomus cells. These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in constitutive Olfr78 knockout mice. In another study, constitutive Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. To further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for maturation of glomus cells.

Forgotten Circulation: Reduced Mesenteric Venous Capacitance in Hypertensive Rats Is Improved by Decreasing Sympathetic Activity.

The mesenteric venous reservoir plays a vital role in mediating blood volume and pressure changes and is richly innervated by sympathetic nerves; however, the precise nature of venous sympathetic regulation and its role during hypertension remains unclear. We hypothesized that sympathetic drive to mesenteric veins in spontaneously hypertensive (SH) rats is raised, increasing mean circulatory filling pressure (MCFP), and impairing mesenteric capacitance. Arterial pressure, central venous pressure, mesenteric arterial, and venous blood flow were measured simultaneously in conscious male Wistar and SH rats. MCFP was assessed using an intraatrial balloon. Hemodynamic responses to volume changes (±20%) were measured before and after ganglionic blockade and carotid body denervation. Sympathetic venoconstrictor activity was measured in situ. MCFP in vivo (10.8±1.6 versus 8.0±2.1 mm Hg; P=0.0005) and sympathetic venoconstrictor drive in situ (18±1 versus 10±2 µV; P<0.0001) were higher in SH rats; MCFP decreased in SH rats after hexamethonium and carotid body denervation (7.6±1.4; P<0.0001 and 8.5±1.0 mm Hg; P=0.0045). During volume changes, arterial pressure remained stable. With blood loss, net efflux of blood from the mesenteric bed was measured in both strains. However, during volume infusion, we observed net influx in Wistar (+2.3±2.6 mL/min) but efflux in SH rats (-1.0±1.0 mL/min; P=0.0032); this counterintuitive efflux was abolished by hexamethonium and carotid body denervation (+0.3±1.7 and 0.5±1.6 mL/min, respectively). In SH rats, excessive sympathetic venoconstriction elevates MCFP and reduces capacitance, impairing volume buffering by mesenteric veins. We propose selective targeting of mesenteric veins through sympathetic drive reduction as a novel therapeutic opportunity for hypertension.

Carotid body dysregulation contributes to Long COVID symptoms

BackgroundThe symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID.MethodsNon-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student’s unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason’s correlation coefficient was used to examine relationships between variables.ResultsDuring cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (−0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (−0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = −0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity.ConclusionsThe carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

The Thirty-Fifth Anniversary of K+ Channels in O2 Sensing: What We Know and What We Don’t Know

On the thirty-fifth anniversary of the first description of O2-sensitive K+ channels in the carotid body chemoreceptors O2 sensing remains a salient issue in the literature. Whereas much has been learned about this subject, important questions such as the identity of the specific K+ channel subtype(s) responsible for O2 sensing by chemoreceptors and the mechanism(s) by which their activities are altered by hypoxia have not yet been definitively answered. O2 sensing is a fundamental biological process necessary for the acute and chronic responses to varying environmental O2 levels which allow organisms to adapt to hypoxia. Whereas chronic responses depend on the modulation of hypoxia-inducible transcription factors which determine the expression of numerous genes encoding enzymes, transporters and growth factors, acute responses rely mainly on the dynamic modulation of ion channels by hypoxia, causing adaptive changes in cell excitability, contractility and secretory activity in specialized tissues. The most widely studied oxygen-sensitive ion channels are potassium channels, but oxygen sensing by members of both the calcium and sodium channel families has also been demonstrated. Given the explosion of information on this topic, in this review, we will focus on the mechanisms of physiological oxygen chemotransduction by PO2-dependent K+ channels, with particular emphasis on their function in carotid body chemoreceptor cells (CBCC) and pulmonary artery smooth muscle cells (PASMC), highlighting areas of consensus and controversy within the field. We will first describe the most well-established concepts, those reproduced in multiple laboratories, and then discuss selected observations or questions that remain unresolved, and that limit our progress in this field.

Thyroid Cancer and Carotid Body Concomitant Tumor: A Case Report

Carotid body tumors are rare neuroendocrine tumors originating from the autonomic nervous system; the annual incidence is approximately 0.8% per 100,000 people per year with a predisposition in females. Papillary thyroid cancer is a type of differentiated cancer derived from the follicular cells of the gland. It has an incidence of 13.5% per 100,000 with a mortality of 0.5% per 100,000 people, affecting women more frequently. The association of papillary thyroid cancer with tumors of the carotid body is uncommon with few cases reported in the literature. Surgery is the main method of therapy for patients with differentiated thyroid cancer. In the hands of expert surgeons, it presents a low risk of complications, offering the patient a good prognosis and a good quality of life. In cases of carotid glomus, surgical resection is chosen in small tumors, in young patients and tumors that do not invade the base of the skull. We present the case of a patient with papillary thyroid cancer associated with carotid paraganglioma that was managed with surgical resolution in a single operation.

Analysis of a Large 19-Year Database in Vascular Surgery in Southern Iran: Evaluation of Trends and Limitations

IntroductionLarge databases with data elements of clinical interest are essential for carrying out high-quality observational studies. Such databases have become increasingly popular for clinical research in fields like Vascular Surgery. Our goal is to create a solid and reliable database of the patients who have been admitted and undergone different vascular-surgery procedures over 19 years and to provide surgeons with the current trends and limitations in managing patients with vascular disease. MethodThe database of patients operated in Namazi Hospital, the referral center for Vascular Surgery in southern Iran, from 2001 to 2019, was retrieved and patients undergoing vascular procedures were parted. Demographic and perioperative data were evaluated and patients were categorized into subgroups based on the type and cause of operation. All data were analyzed with SPSS version 26.0 (IBM. NY. USA). ResultsDuring the period of our study, a total of 226,051 operations were performed at the Namazi Hospital. Among these operations, 6,386 (2.82%) Vascular Surgery-related operations were entered into our study. The average age of the patients in our study was 53.22 ± 18.92 years (range: 1 day old – 97 years) and 4,061 (63.6%) were male. Furthermore, 147 (2.3%) were operated by multiple surgeons. Moreover, 798 (12.5%) of the patients were admitted postoperatively to the intensive care unit (ICU), while the rest (5,588; 87.5%) in the common surgery ward. The cause of operation in 609 (9.5%) of the cases was trauma. Based on wound categorization, 5,132 (80.4%) were type I (clean). The most frequent operation performed in our center was arterial reconstruction and limb revascularization (31.4%), followed by hemodialysis access (31.3%). The most frequent surgery in the age group of under 18 years was fasciotomy, in the 19 to 40 years group was tumor (56.8%) and varicose veins (52.9%), in the 41 to 60 years group was implantation of ventral venous port catheter (47%). Only carotid and thoracic outlet syndrome surgeries were significantly higher in females. The remaining operations were all significantly higher among male patients. Finally, carotid body tumor surgery was the most frequent operation requiring ICU monitoring. ConclusionWe demonstrated, for the first time, an overview of Vascular Surgeries performed in a referral tertiary center in Southwest Iran. There is an increase in the number of surgical procedures in the field of Vascular Surgery, and large databases will be a valuable tool for addressing critical problems in this field and also the healthcare system.

Hypoxic Signaling Pathways in Carotid Body Tumors

Carotid body tumors (CBTs) are rare tumors with a 1–2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak–Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs.

Blood oxygen regulation via P2Y12R expressed in the carotid body

BackgroundPeripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown.MethodsThe presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizing OGB-1 and N-STORM Super-Resolution System. Ingravescent hypoxia model was tested in anaesthetized mice of mixed gender and cardiorespiratory parameters were recorded in control and receptor-deficient or drug-treated experimental animals.ResultsInitially, the expression of P2Y12R in adult murine CB was confirmed. Hypoxia induced a P2Y12R-dependent release of monoamine transmitters from isolated CB cells. Receptor activation with the endogenous ligand ADP promoted release of neurotransmitters under normoxic conditions, while blockade disrupted the amplitude and duration of the intracellular calcium concentration. In anaesthetised mice, blockade of P2Y12R expressed in the CB abrogated the initiation of compensatory cardiorespiratory changes in hypoxic environment, while centrally inhibited receptors (i.e. microglial receptors) or receptor-deficiency induced by platelet depletion had limited influence on the physiological adjustment to hypoxia.ConclusionsPeripheral P2Y12R inhibition interfere with the complex mechanisms of acute oxygen sensing by influencing the calcium signalling and the release of neurotransmitter molecules to evoke compensatory response to hypoxia. Prospectively, the irreversible blockade of glomic receptors by anti-platelet drugs targeting P2Y12Rs, propose a potential, formerly unrecognized side-effect to anti-platelet medications in patients with pulmonary morbidities.