Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility

Lechauve, Christophe; Butcher, Joshua T.; Freiwan, Abdullah; Biwer, Lauren A; Keith, Julia; Good, Miranda E.; Ackerman, Hans; Tillman, Heather; Kiger, Laurent; Isakson, Brant E.; Weiss, Mitchell J.

doi:10.1172/jci99933

Cited by 43 publications

(59 citation statements)

References 59 publications

(88 reference statements)

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“…NOS g may participate in such a function. Globin-based regulation of NOS has precedent in animals; eNOS binds to and stabilizes ␣-globin at the myoendothelial junction so that ␣-globin can regulate NO signaling by oxidizing NO to nitrate (69). Additionally, in vitro experiments found that full-length eNOS was able to reduce ␣-globin to the active ferrous state at a faster rate than the methemoglobin reductase cytochrome B5 reductase (69).…”

Section: Discussionmentioning

confidence: 99%

A nitric oxide synthase–like protein from Synechococcus produces NO/NO3− from l-arginine and NAPDH in a tetrahydrobiopterin- and Ca2+-dependent manner

Picciano

Crane

2019

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

A nitric oxide synthase–like protein from Synechococcus produces NO/NO3− from l-arginine and NAPDH in a tetrahydrobiopterin- and Ca2+-dependent manner

Picciano

Crane

2019

Journal of Biological Chemistry

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“…Neonatal polycythemia is a common complication associated with maternal diabetes, and it is possible that higher expression of Ahsp and Kel are due to a higher number of residual red cells in the myocardial vasculature within our samples. However, Ahsp and Kel are found in other tissue such as endothelial cells, including coronary arteries where they reportedly regulate vasoconstriction through the oxygen sensing eNOS and endothelin-3 activation, respectively (83,84). It is plausible these expression differences convey commonly reported vascular manifestations in offspring of diabetic mothers (33,85).…”

Section: Discussionmentioning

confidence: 99%

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

et al. 2020

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Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes-and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on regulation of heart health.

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“…39 Alpha globin has been shown to complex with eNOS to regulate NO-signaling in the resistance vasculature. 24,25 Its expression at the MEJ may act to finely control vasodilation by limiting the diffusion of eNOS-derived NO to the SMC. 39 Contact between ECs and SMCs is required for the expression of alpha globin in ECs 23,40 , and in the newly formed EC projections that resulted from PAI-1 treatment, alpha globin expression is significantly increased which correlated with limited dilatory effect of NO ( Figure 4H).…”

Section: Discussionmentioning

confidence: 99%

“…15,[20][21][22][23] In contrast, the expression of alpha globin in endothelial cells of resistance arteries may provide a constraint on the ability of NO to diffuse from endothelium to smooth muscle, limiting the role of NO in this setting. [23][24][25] Our lab has previously demonstrated that plasminogen activator inhibitor-1 (PAI-1) is enriched at the MEJ and that its depletion results in decreased MEJ formation. 26,27 However, it remains to be demonstrated whether PAI-1 is sufficient to induce MEJ formation.…”

Section: Introductionmentioning

confidence: 99%

Heterocellular Contact Can Dictate Arterial Function

Shu

Ruddiman

Keller

et al. 2019

Circulation Research

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Rationale: Resistance arteries and conduit arteries rely upon different relative contributions of endothelial derived hyperpolarization (EDH) versus nitric oxide (NO) to achieve dilatory heterocellular signaling. Anatomically, resistance arteries use myoendothelial junctions (MEJs), endothelial cell (EC) projections that make contact with smooth muscle cells (SMCs). Conduit arteries have very few to no MEJs. Objective: Determine if the presence of MEJs in conduit arteries can alter heterocellular signaling. Methods and Results: We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1) can regulate formation of MEJs. Thus, we applied pluronic gel containing PAI-1 directly to conduit arteries (carotid arteries, CAs) to determine if this could induce formation of MEJs. We found a significant increase in EC projections resembling MEJs that correlated with increased biocytin dye transfer from ECs to SMCs. Next, we used pressure myography to investigate whether these structural changes were accompanied by a functional change in vasodilatory signaling. Interestingly, PAI-1-treated CAs underwent a switch from a conduit to resistance artery vasodilatory profile via diminished NO signaling, and increased EDH signaling in response to the endothelium-dependent agonists Ach and NS309. Following PAI-1 application, we also found a significant increase in carotid expression of endothelial alpha globin, a protein predominantly expressed in resistance arteries. Carotids from mice with PAI-1, but lacking alpha globin (Hba1 −/−), demonstrated that L-NAME, an inhibitor of NO signaling, was able to prevent arterial relaxation.

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Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility

Cited by 43 publications

References 59 publications

A nitric oxide synthase–like protein from Synechococcus produces NO/NO3− from l-arginine and NAPDH in a tetrahydrobiopterin- and Ca2+-dependent manner

A nitric oxide synthase–like protein from Synechococcus produces NO/NO3− from l-arginine and NAPDH in a tetrahydrobiopterin- and Ca2+-dependent manner

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

Heterocellular Contact Can Dictate Arterial Function

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