Morita T, Kourembanas S
Joint Program in Neonatology, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Clin Invest. 1995 Dec;96(6):2676-82. doi: 10.1172/JCI118334.
CO is produced in vascular smooth muscle cells (VSMC) by heme oxygenase-1 (HO-1). CO increases cGMP levels in VSMC; however, its possible additional roles in the vasculature have not been examined. We report that a product of HO, released from VSMC and inhibited by hemoglobin, has paracrine effects on endothelial cells: it increases endothelial cGMP content and decreases the expression of the mitogens, endothelin-1 (ET-1) and platelet-derived growth factor-B (PDGF-B). This product has the characteristics of CO, and its production is increased sevenfold under hypoxia. The VSMC-derived CO caused a fourfold rise in endothelial cell cGMP. In addition, it inhibited the hypoxia-induced increases in mRNA levels of the ET-1 and PDGF-B genes. Inhibitors of HO, and hemoglobin, a scavenger of CO, prevented the rise in cGMP and also restored the hypoxic response of these genes. The inhibition of ET-1 and PDGF-B mRNA by CO resulted in decreased production of these endothelial-derived mitogens, and in turn, inhibition of VSMC proliferation. These findings suggest an important physiologic role for VSMC-derived CO in modulating cell-cell interaction and cell proliferation in the vessel wall during hypoxia.
一氧化碳（CO）由血红素加氧酶-1（HO-1）在血管平滑肌细胞（VSMC）中产生。CO可提高VSMC中的环磷酸鸟苷（cGMP）水平；然而，其在脉管系统中可能存在的其他作用尚未得到研究。我们报告称，一种由VSMC释放、可被血红蛋白抑制的HO产物，对内皮细胞具有旁分泌作用：它可增加内皮细胞中的cGMP含量，并降低有丝分裂原内皮素-1（ET-1）和血小板衍生生长因子-B（PDGF-B）的表达。该产物具有CO的特性，在缺氧条件下其生成量增加7倍。VSMC衍生的CO使内皮细胞中的cGMP升高了4倍。此外，它抑制了缺氧诱导的ET-1和PDGF-B基因mRNA水平的升高。HO抑制剂和CO清除剂血红蛋白可阻止cGMP升高，并恢复这些基因的缺氧反应。CO对ET-1和PDGF-B mRNA的抑制导致这些内皮衍生有丝分裂原的产生减少，进而抑制VSMC增殖。这些发现表明，VSMC衍生的CO在缺氧期间调节血管壁中的细胞间相互作用和细胞增殖方面具有重要的生理作用。
