Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability

Diana Raisovna Gutsaeva, Pedro Montero-Huerta, James B. Parkerson, Shobha D. Yerigenahally, Tohru Ikuta, C. Alvin Head

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The molecular mechanisms by which nitric oxide (NO) bioavailability modulates the clinical expression of sickle cell disease (SCD) remain elusive. We investigated the effect of hypoxia and NO bioavailability on sickle red blood cell (sRBC) adhesion using mice deficient for endothelial NO synthase (eNOS) because their NO metabolite levels are similar to those of SCD mice but without hypoxemia. Whereas sRBC adhesion to endothelial cells in eNOS-deficient mice was synergistically upregulated at the onset of hypoxia, leukocyte adhesion was unaffected. Restoring NO metabolite levels to physiological levels markedly reduced sRBC adhesion to levels seen under normoxia. These results indicate that sRBC adherence to endothelial cells increases in response to hypoxia prior to leukocyte adherence, and that low NO bioavailability synergistically upregulates sRBC adhesion under hypoxia. Although multiple adhesion molecules mediatesRBCadhesion,wefound a central role for P-selectin insRBCadhesion. Hypoxia and low NO bioavailability upregulated P-selectin expression in endothelial cells in an additive manner through p38 kinase pathways. These results demonstrate novel cellular and signaling mechanisms that regulate sRBC adhesion under hypoxia and low NObioavailability. Importantly, these findings point us toward newmolecular targets to inhibit cell adhesion in SCD.

Original languageEnglish (US)
Pages (from-to)1917-1926
Number of pages10
JournalBlood
Volume123
Issue number12
DOIs
StatePublished - Mar 20 2014

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Cell Hypoxia
Cell adhesion
Biological Availability
Cell Adhesion
Nitric Oxide
Blood
Adhesion
Erythrocytes
Cells
Endothelial cells
Sickle Cell Anemia
P-Selectin
Metabolites
Endothelial Cells
Leukocytes
Nitric Oxide Synthase Type III
MAP Kinase Signaling System
Nitric Oxide Synthase
Hypoxia
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability. / Gutsaeva, Diana Raisovna; Montero-Huerta, Pedro; Parkerson, James B.; Yerigenahally, Shobha D.; Ikuta, Tohru; Head, C. Alvin.

In: Blood, Vol. 123, No. 12, 20.03.2014, p. 1917-1926.

Research output: Contribution to journalArticle

Gutsaeva, Diana Raisovna ; Montero-Huerta, Pedro ; Parkerson, James B. ; Yerigenahally, Shobha D. ; Ikuta, Tohru ; Head, C. Alvin. / Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability. In: Blood. 2014 ; Vol. 123, No. 12. pp. 1917-1926.
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