Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation

Abstract

. Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation. Am J Physiol Heart Circ Physiol 286: H222-H229, 2004. First published September 25, 2003 10.1152/ajpheart.00532.2003.-The effects of enhanced red blood cell (RBC) aggregation on nitric oxide (NO)-dependent vascular control mechanisms have been investigated in a rat exchange transfusion model. RBC aggregation for cells in native plasma was increased via a novel method using RBCs covalently coated with a 13-kDa poloxamer copolymer (Pluronic F-98); control experiments used RBCs coated with a nonaggregating 8.4-kDa poloxamer (Pluronic F-68). Rats exchange transfused with aggregating RBC suspensions demonstrated significantly enhanced RBC aggregation throughout the 5-day follow-up period, with mean arterial blood pressure increasing gradually over this period. Arterial segments (Ϸ300 m in diameter) were isolated from gracilis muscle on the fifth day and mounted between two glass micropipettes in a special chamber equipped with pressure servo-control system. Dose-dependent dilation by ACh and flow-mediated dilation of arterial segments pressurized to 30 mmHg and preconstricted to 45-55% of the original diameter by phenylephrine were significantly blunted in rats with enhanced RBC aggregation. Both responses were totally abolished by nonspecific NO synthase (NOS) inhibitor (N -nitro-L-arginine methyl ester) treatment of arterial segments, indicating that the responses were NO related. Additionally, expression of endothelial NOS protein was found to be decreased in muscle samples obtained from rats exchanged with aggregating cell suspensions. These results imply that enhanced RBC aggregation results in suppressed expression of NO synthesizing mechanisms, thereby leading to altered vasomotor tonus; the mechanisms involved most likely relate to decreased wall shear stresses due to decreased blood flow and/or increased axial accumulation of RBCs. flow-mediated dilation; poloxamer coating NITRIC OXIDE (NO) plays a key role in the control of circulatory function (21), and the importance of NO in the regulation of vascular smooth muscle tone and the maintenance of vascular resistance has been well established (13,38,44). In addition, several other physiological functions (e.g., apoptosis) have been attributed to this simple molecule (9, 25). Endothelial cells are the source of NO that modulates vascular resistance: NO diffuses to the underlying vascular smooth muscle where it activates guanylate cyclase to increase cGMP, thus resulting in smooth muscle relaxation (26) and decreased vascular resistance.Endothelial NO is synthesized by the endothelial isoform of NO synthase (eNOS) using L-arginine as substrate (31). While eNOS is continuously expressed at a basal level in endothelial cells, its activation is dependent on Ca 2ϩ /calmodulin complex levels, and thus NO generation by endothelial cells is dependent on intracellular calcium concentration (41). It has been shown that this calcium-dependent regulation of NO synthesis in endothe...

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