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Redox-Regulation of α-Globin in Vascular Physiology.

ABSTRACT: Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe²⁺) α-globin to the oxidized (Fe³⁺) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe³⁺) α-globin must be stabilized and recycled to (Fe²⁺) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe³⁺) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe³⁺) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b₅ reductase (CyB5R3) with cytochrome b₅ type A (CyB5a) can reduce (Fe³⁺) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility.

SUBMITTER: Kiger L

PROVIDER: S-EPMC8773178 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We present the first evidence for vascular regulation driving fMRI signals in specific functional brain networks. Using concurrent neuronal and vascular stimuli, we collected 30 BOLD fMRI datasets in 10 healthy individuals: a working memory task, flashing checkerboard stimulus, and CO2 inhalation challenge were delivered in concurrent but orthogonal paradigms. The resulting imaging data were averaged together and decomposed using independent component analysis, and three "neuronal networks" were identified as demonstrating maximum temporal correlation with the neuronal stimulus paradigms: Default Mode Network, Task Positive Network, and Visual Network. For each of these, we observed a second network component with high spatial overlap. Using dual regression in the original 30 datasets, we extracted the time-series associated with these network pairs and calculated the percent of variance explained by the neuronal or vascular stimuli using a normalized R2 parameter. In each pairing, one network was dominated by the appropriate neuronal stimulus, and the other was dominated by the vascular stimulus as represented by the end-tidal CO2 time-series recorded in each scan. We acquired a second dataset in 8 of the original participants, where no CO2 challenge was delivered and CO2 levels fluctuated naturally with breathing variations. Although splitting of functional networks was not robust in these data, performing dual regression with the network maps from the original analysis in this new dataset successfully replicated our observations. Thus, in addition to responding to localized metabolic changes, the brain's vasculature may be regulated in a coordinated manner that mimics (and potentially supports) specific functional brain networks. Multi-modal imaging and advances in fMRI acquisition and analysis could facilitate further study of the dual nature of functional brain networks. It will be critical to understand network-specific vascular function, and the behavior of a coupled vascular-neural network, in future studies of brain pathology.

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Redox-Regulation of α-Globin in Vascular Physiology.

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