Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature.
Hypoxia has profound effects on blood vessel tone. Acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia causes smooth muscle cell replication and extracellular matrix accumulation resulting in vessel wall remodeling. The cellular responses to hypoxia involve complex cell-cell interactions mediated by the release of growth factors, cytokines and biological messengers. We have reported that hypoxia increases the expression of a number of genes encoding vascular cell mitogens produced by endothelial cells: platelet-derived growth factor B (PDGF-B); endothelin-1 (ET-1); and vascular endothelial growth factor (VEGF). A 28-bp enhancer in the 5' upstream region of the VEGF gene mediates the expression of VEGF by endothelial cells under conditions of hypoxia. Hypoxia, however, has opposite effects on the vasodilator nitric oxide (NO); hypoxia suppresses both the transcriptional rate of the endothelial nitric oxide synthase gene and the stability of its mRNA. These endothelial-dependent processes would lead to vessel wall remodeling characteristic of a number of diseases from atherosclerosis to pulmonary hypertension. The smooth muscle cell also responds to hypoxia. It increases the transcriptional rate of the heme oxygenase gene-1 responsible for the breakdown of heme to carbon monoxide (CO) and biliverdin. CO is a vasodilator with properties similar to the well-studied molecule NO. CO suppresses the production of ET-1 and PDGF-B by endothelial cells. The regulated production of NO and CO under hypoxia, therefore, results in complex feedback loop interactions leading to altered smooth muscle cell growth in an autocrine and paracrine manner.
Kourembanas
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Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. kourembanas@a1.teh.harvard.edu
Morita
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T
Liu
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Y
Christou
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H
D000818:Animals; D001483:Base Sequence; D002248:Carbon Monoxide / Q000378:metabolism; D002417:Cattle; D002450:Cell Communication; D002478:Cells, Cultured; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000235:genetics; D010101:Oxygen Consumption; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D019332:Endothelin-1; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D002248:Carbon Monoxide; D004247:DNA