VASCULAR CELL-ADHESION MOLECULE-1 IS INVOLVED IN MEDIATING HYPOXIA-INDUCED SICKLE RED-BLOOD-CELL ADHERENCE TO ENDOTHELIUM - POTENTIAL ROLE IN SICKLE-CELL DISEASE

We investigated the effects of hypoxia on red blood cell (RBC)-endothe lial cell (EC) adherence and the potential mechanism(s) involved in me diating this effect. We report that hypoxia significantly increased si ckle RBC adherence to aortic EC when compared with the normoxia contro ls, However, hypoxia had no effect on the adherence of normal RBCs. In additional studies, we found that the least dense sickle RBCs contain ing CD36(+) and VLA-4(+) reticulocytes were involved in hypoxia-induce d adherence. We next evaluated the effects of hypoxia on the expressio n of EC surface receptors involved in RBC adherence to macrovascular E Cs, including vascular cell adhesion molecule-1 (VCAM-1), intracellula r adhesion molecule-1 (ICAM-1), and the vitronectin receptor (VnR). Hy poxia upregulated the expression of both VCAM-1 and ICAM-1, whereas no effect on VnR was noted. Potential involvement of VCAM-1 and ICAM-1 i n mediating hypoxia-induced sickle RBC-EC adhesion was next investigat ed using monoclonal antibodies against these receptors. Whereas anti-V CAM-1 had no effect on basal adherence, it inhibited hypoxia-induced s ickle RBC adherence in a concentration-dependent manner, with 50% to 7 5% inhibition noted at 10 to 60 mu g/mL antibody (n = 6, P < .05 to P < .01). Anti-ICAM-1 (10 to 60 mu g/mL, n = 8) had no affect on either basal or hypoxia induced adherence. As noted in the bovine aortic ECs, hypoxia stimulated the adherence of sickle RBCs to human retinal capi llary ECs, and this response appeared to be mediated via mechanisms si milar to those observed with macro-endothelium, is, via the adhesive r eceptor combination VCAM-1-VLA-4. Our studies show that hypoxia enhanc es sickle RBC adhesion to both macrovascular and human microvascular E Cs via the adhesive receptor VCAM-1. Our findings are of interest beca use hypoxia is an integral part of the pathophysiology of the vaso-occ lusive phenomenon in sickle cell anemia. (C) 1996 by The American Soci ety of Hematology.