Hypoxia and carbon monoxide in the vasculature.
Hypoxia is sensed by all mammalian cells and elicits a variety of adaptive and pathophysiological responses at the molecular and cellular level. For the pulmonary vasculature, hypoxia causes increased vasoconstriction and vessel-wall remodeling. These responses are mediated by complex intracellular cascades leading to altered gene expression and cell-cell interaction. Hypoxia transiently increases the transcriptional rate of the heme oxygenase-1 (HO-1) gene, resulting in increased production of carbon monoxide (CO) and bilirubin. CO has vasodilatory and antiinflammatory properties in the vasculature, whereas bilirubin is an antioxidant. Both enzymatic products could thus modulate the hypoxic cellular response. Accumulating data suggest that CO inhibits the hypoxic induction of genes encoding vasoconstrictors and smooth muscle cell mitogens in the early hypoxic phase. During chronic hypoxia, low CO levels tilt the balance toward increased production of growth factors and vasoconstrictors that promote vessel-wall remodeling. Mice null in the HO-1 gene manifest decreased tolerance to hypoxia with right ventricular dilatation and infarction, whereas targeted lung overexpression of HO-1 prevents hypoxia-induced inflammatory responses and protects against the development of pulmonary hypertension. Such observations point to CO as a critical modulator of the body's adaptive responses to hypoxia.
Kourembanas
Stella
S
Department of Medicine, Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. stella.kourembanas@tch.harvard.edu
D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D002248:Carbon Monoxide / Q000502:physiology*; D015687:Cell Hypoxia; D004730:Endothelium, Vascular / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000502:physiology*
D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)