Endothelial dysfunction in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a rare disease caused by functional and structural abnormalities in distal pulmonary arterioles that result in progressive increases in pulmonary vascular resistance, often leading to right heart failure and death. Endothelial dysfunction, defined as a shift in the balance of production of endothelial vasodilator factors (i.e., nitric oxide and prostacyclin), and vasoconstrictor and proliferative factors (i.e., endothelin-1 and thromboxane A2), has been strongly implicated in PAH. Here we review the evidence supporting a central role for endothelial dysfunction in the pathogenesis of PAH as a result of genetic and environmental influences, and extend this concept to include the critical balance between pathways for endothelial growth and survival. In addition, we present support for the hypothesis that the initial loss of endothelial cells, largely by apoptosis, an extreme form of endothelial dysfunction, triggers a cascade of events that ultimately result in the typical, complex constellation of functional and structural lung vascular abnormalities, including formation of the proliferative intimal and plexiform lesions. This novel paradigm may help in the design of strategies that better address the root cause of PAH and may possibly lead to more effective treatments.