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Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility
Christophe Lechauve, … , Brant E. Isakson, Mitchell J. Weiss
Christophe Lechauve, … , Brant E. Isakson, Mitchell J. Weiss
Published October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):5073-5082. https://doi.org/10.1172/JCI99933.
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Research Article Hematology Vascular biology

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

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Abstract

Arteriolar endothelial cell–expressed (EC-expressed) α-globin binds endothelial NOS (eNOS) and degrades its enzymatic product, NO, via dioxygenation, thereby lessening the vasodilatory effects of NO on nearby vascular smooth muscle. Although this reaction potentially affects vascular physiology, the mechanisms that regulate α-globin expression and dioxygenase activity in ECs are unknown. Without β-globin, α-globin is unstable and cytotoxic, particularly in its oxidized form, which is generated by dioxygenation and recycled via endogenous reductases. We show that the molecular chaperone α-hemoglobin–stabilizing protein (AHSP) promotes arteriolar α-globin expression in vivo and facilitates its reduction by eNOS. In Ahsp−/− mice, EC α-globin was decreased by 70%. Ahsp−/− and Hba1−/− mice exhibited similar evidence of increased vascular NO signaling, including arteriolar dilation, blunted α1-adrenergic vasoconstriction, and reduced blood pressure. Purified α-globin bound eNOS or AHSP, but not both together. In ECs in culture, eNOS or AHSP enhanced α-globin expression posttranscriptionally. However, only AHSP prevented oxidized α-globin precipitation in solution. Finally, eNOS reduced AHSP-bound α-globin approximately 6-fold faster than did the major erythrocyte hemoglobin reductases (cytochrome B5 reductase plus cytochrome B5). Our data support a model whereby redox-sensitive shuttling of EC α-globin between AHSP and eNOS regulates EC NO degradation and vascular tone.

Authors

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

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Figure 4

Ahsp or Hba1 gene disruption inhibits vasoconstriction after α1-adrenergic stimulation and reduces systemic blood pressure.

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Ahsp or Hba1 gene disruption inhibits vasoconstriction after α1-adrener...
Mice with the indicated genotypes were lethally irradiated, transplanted with WT hematopoietic stem and progenitor cells to restore normal RBC production, and examined 6 to 8 weeks later. (A) Vasoconstriction of TDAs from control (n = 7) and mutant (Ahsp−/−, n = 9; Hba1−/−, n = 6) mice after treatment with escalating doses of PE, with or without the eNOS inhibitor L-NAME (Ahsp−/− ± L-NAME, n = 4; Hba1−/− ± L-NAME, n = 3). (B) Mean arterial blood pressures of mice with the indicated genotypes measured by radiotelemetry (control, n = 11; Ahsp−/−, n = 7; Hba1−/−, n = 5). *P < 0.05 and ****P < 0.001, by 2-way ANOVA (A) and unpaired t test (B).
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