title: Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability.
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 mediate sRBC adhesion, we found a central role for P-selectin in sRBC adhesion. 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 NO bioavailability. Importantly, these findings point us toward new molecular targets to inhibit cell adhesion in SCD.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Gutsaeva
authors.forename: Pedro
authors.initials: P
authors.lastname: Montero-Huerta
authors.forename: James B
authors.initials: JB
authors.lastname: Parkerson
authors.forename: Shobha D
authors.initials: SD
authors.lastname: Yerigenahally
authors.forename: Tohru
authors.initials: T
authors.lastname: Ikuta
authors.forename: C Alvin
authors.initials: CA
authors.lastname: Head
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D004913:Erythrocytes, Abnormal / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000097:blood*; D052250:Nitric Oxide Synthase Type III / Q000097:blood / Q000172:deficiency / Q000235:genetics; D019007:P-Selectin / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019007:P-Selectin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases