Structural basis of hypoxic pulmonary hypertension: the modifying effect of chronic hypercapnia

Exposure to chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodelling. In chronic lung disease, chronic hypercapnia frequently coexists with hypoxia and is associated with worsening of pulmonary hypertension. It is generally stated that pulmonary hypertension in these conditions is secondary to hypoxic vascular remodelling and that hypercapnia augments this remodelling thus worsening the hypertension. We review recent evidence which shows that although chronic hypoxia causes thickening of the walls of pulmonary arterioles, these changes do not lead to structural narrowing of the lumen by encroachment. Moreover, hypoxia leads to new vessel formation within the pulmonary vasculature and not loss of vessels as formerly thought. Such neovascularization may provide a beneficial adaptation by increasing the area of the gas exchange membrane. These novel structural findings are supported by recent reports that inhibitors of the RhoA pathway can acutely reduce pulmonary vascular resistance in chronically hypoxic lungs to near normal values, demonstrating that structural changes are not the dominant mechanisms underling hypoxic pulmonary hypertension. Chronic hypercapnia inhibits the development of hypoxic pulmonary hypertension, pulmonary vascular remodelling and hypoxia-induced angiogenesis. This last effect might be maladaptive, as it would prevent the potentially beneficial increase in gas exchange membrane area. These findings suggest that structural narrowing of the vascular lumen of resistance vessels is not the mechanism by which hypoxia and hypercapnia cause pulmonary hypertension in chronic lung disease.