Spinal Oxygen Sensors (SOS): A Novel Oxygen Sensing Mechanism Involved in Cardiovascular Responses to Hypoxia
Bibliographic record
Abstract
BACKGROUND In healthy individuals, when blood oxygenation decreases, cardiorespiratory reflexes are triggered in an attempt to restore oxygen supply to vital organs. The carotid bodies are the primary respiratory oxygen chemoreceptors but cardiovascular responses to hypoxia such as increase in heart rate and blood pressure persist in their absence, suggesting an additional high‐fidelity oxygen sensor. Previously we discovered that spinal sympathetic preganglionic neurons (SPN), are exquisitely sensitive to oxygen; here we investigate the oxygen sensing mechanisms and test the role of these spinal oxygen sensors (SOS) in cardiorespiratory responses to asphyxia‐like stimuli. OBJECTIVE To study the cellular oxygen sensing mechanism and contribution of the SOS in responses to cardiorespiratory crisis. METHODS We investigated the cellular mechanism of oxygen sensing in artificially‐perfused ( in situ ) and slice ( in vitro ) thoracic spinal cord preparations, recording sympathetic nerve root and single cell responses to hypoxia during pharmacological interrogation. To determine if the SOS are involved in cardiorespiratory responses to asphyxia, we also used an in situ rat spinal cord – carotid body ‐ brainstem preparation in which each oxygen sensitive compartment is separately perfused while recording phrenic (respiratory) and splanchnic (sympathetic) nerve activity. RESULTS Our data suggest the SOS use a novel oxygen sensing mechanism. This mechanism involves two interacting NADPH and oxygen‐dependent enzymes: Neuronal Nitric Oxide Synthase (NOS1) and NADPH oxidase (NOX2). NOS1 is expressed in surprising abundance in the SOS and is oxygen sensitive across the entire physiological range. Hence, in the presence of oxygen, NOS1 is likely to utilize most of the available NADPH in the cell. When oxygenation falls during hypoxia, NOS1 activity is reduced, increasing NADPH availability for NOX2. NOX2 produces Reactive Oxygen Species (ROS) which in turn, activate ROS‐dependent internal Ca 2+ stores and/or Ca 2+ channels leading to increased intracellular Ca 2+ , neuronal firing and, consequently, SOS responses to hypoxia. Functionally, during hypoxia, the SOS enhance sympathetic and breathing activity, while shortening apnea and gasping towards recovery, and are capable of triggering brief periods of sympathetic and respiratory‐like activity in the brainstem’s absence. CONCLUSIONS The results provide critical new knowledge required to unlock the cellular mechanisms involved in how the body mounts emergency responses to conditions that involve chronic and acute hypoxia. Support or Funding Information University of Calgary Eyes High; Hotchkiss Brain Institute; Alberta Children’s Hospital Research Institute; Alberta Innovates Health Solutions; MITACS Globalink; Canadian Institutes of Health Research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".