Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide.
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.
Morita
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Joint Program in Neonatology, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kourembanas
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D000704:Analysis of Variance; D000818:Animals; D001011:Aorta; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D018920:Coculture Techniques; D016232:Endothelins / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006454:Hemoglobins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014471:Umbilical Veins
D016232:Endothelins; D004791:Enzyme Inhibitors; D006133:Growth Substances; D006454:Hemoglobins; D012333:RNA, Messenger; D019335:Nitroarginine; D002248:Carbon Monoxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing)