Endothelial cell responses to hypoxic stress.

1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes. 2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue. 3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF-B, endothelin-1, VEGF, thrombospondin-1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP-9), thrombospondin-1) and reciprocal transcriptional inhibition of vasodilatory or anti-mitogenic effectors (eNOS). 4. Oxygen appears to signal through a novel haem-containing sensor and signals initiated by this sensor alter the levels and DNA-binding activity of transcription factors such as activating protein (AP)-1, nuclear factor-kappa B and hypoxia-inducible transcription factor-1. 5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO). 6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types). 7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia. 8. Short-term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer-term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling. 9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short-term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis. 10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).