Endothelial injuries of coronary arteries distal to thrombotic sites - Role of adhesive interaction between endothelial P-selectin and leukocyte sialyl Lewis(X)

Intracoronary thrombus formation is associated with epicardial vasoconstric tion distal to the thrombotic site. To investigate the mechanisms of abnorm al vasomotor function of the artery distal to the thrombotic site, we studi ed coronary vessels in dogs with cyclic flow variations (CFVs) of the left anterior descending coronary artery (LAD) stenosis with endothelial injury, Coronary rings isolated from the LAD (proximal, stenotic, and distal sites ) and control circumflex coronary arteries were tested for responsiveness t o endothelium-dependent (acetylcholine and A23187) and endothelium-independ ent vasodilators (NaNO2). Endothelium-independent relaxation was intact in all 4 sites. Endothelium-dependent relaxation was intact in the control and proximal sites and impaired in the stenotic sites. Relaxations not only to acetylcholine and A23187 but also to serotonin, ADP, and thrombin were imp aired in the distal sites after observing CFVs for 80 minutes. Electron mic roscopy revealed the loss of endothelial integrity with leukocyte adherence to the endothelium in the distal sites. Immunohistochemical expression of P-selectin on the endothelial cells was more upregulated in the distal site than in the proximal site, and P-selectin mRNA expression was significantl y greater in the ischemic region distal to the thrombotic site than in the proximal nonischemic region. PB1.3, a neutralizing monoclonal antibody agai nst P-selectin, and sialyl Lewis(x) (SLe(x))-containing oligosaccharide SLe (x), a carbohydrate analogue of selectin ligand, preserved endothelial func tion without affecting CFVs. SLe(x)-containing oligosaccharide preserved en dothelial integrity of the distal site and inhibited P-selectin expression of the distal site. Thus, the adhesive interaction between endothelial P-se lectin and leukocyte SLe(x) may play an important role in endothelial injur ies of the coronary artery distal to the thrombotic site.