Phelan M, Perrine S P, Brauer M, Faller D V
Cancer Research Center, Boston University Medical Center, Massachusetts 02118, USA.
J Clin Invest. 1995 Aug;96(2):1145-51. doi: 10.1172/JCI118102.
The molecular defect in sickle cell disease resides in the beta globin gene, with consequent defects in erythrocytes only, suggesting that the vascular occlusion and vasomotor instability which characterize this disease are the result of interactions between abnormal sickle erythrocytes and cells of the blood vessel wall. We explored whether sickle erythrocytes may have effects on vascular tone, exclusive of adhesion events. Exposure of human endothelial cells in culture to previously sickled sickle erythrocytes resulted in a four to eight-fold transcriptional induction of the gene encoding the potent vasoconstrictor endothelin-1 (ET-1). Unsickled sickle erythrocytes or normal erythrocytes exposed to "sickling" conditions had no effect on ET-1 gene induction. Contact of the sickled erythrocytes with the endothelium was not required. Elevations in the ET-1 transcript peaked at 3 h after exposure and persisted for up to 24 h. Four to sixfold increases in the amount of ET-1 peptide was released into the medium surrounding the endothelial cells after exposure to sickled sickle erythrocytes. This is the first demonstration of the regulation of gene expression in endothelial cells as a result of interaction with sickle cells, with induction of genes encoding vasoconstrictors. Furthermore, these findings suggest that sickle erythrocytes may have the capacity to affect local vasomotor tone directly.
镰状细胞病的分子缺陷存在于β珠蛋白基因中，仅导致红细胞出现缺陷，这表明该疾病所特有的血管闭塞和血管舒缩不稳定是异常镰状红细胞与血管壁细胞之间相互作用的结果。我们探究了镰状红细胞是否可能对血管张力产生影响，而不涉及黏附事件。将培养中的人内皮细胞暴露于先前已镰变的镰状红细胞中，导致编码强效血管收缩剂内皮素-1（ET-1）的基因转录诱导增加了4至8倍。未镰变的镰状红细胞或暴露于“镰变”条件下的正常红细胞对ET-1基因诱导没有影响。镰状红细胞与内皮细胞的接触并非必需。ET-1转录本的升高在暴露后3小时达到峰值，并持续长达24小时。暴露于镰状红细胞后，内皮细胞周围培养基中释放的ET-1肽量增加了4至6倍。这是首次证明内皮细胞因与镰状细胞相互作用而导致基因表达受到调控，并诱导了编码血管收缩剂的基因。此外，这些发现表明镰状红细胞可能有能力直接影响局部血管舒缩张力。
