A receptor and its trigger have been accused of causing a fatal form of lung hypertension, but that could be a bum rap. These molecules actually curb pressure increases in lung arteries and help shield these delicate vessels, Kugathasan et al. conclude.

The children and young adults who develop pulmonary artery hypertension (PAH), excessive pressure in the vessel that pipes blood from the heart to the lungs, usually die within two to five years. The Angiopoeitin-1 (Ang1)/Tie2 pathway seems to be involved in the illness. Tie2 is a surface receptor that spurs angiogenesis before and after birth. And Tie2's ligand, Ang1, guards endothelial cells from inflammation and forestalls apoptosis. However, previous studies have clashed about the effects of this pathway on PAH. After reporting excess Ang1 and high Tie2 activity in samples from patients' lungs, some researchers argued that the pathway exacerbates the illness. But other work has since shown that Ang1 might be just as abundant in healthy lungs and that the pathway might protect vascular cells.

To resolve these contradictions, Kugathasan et al. engineered mice with half the normal amount of Tie2. The animals' right ventricular systolic pressure—an indicator of pulmonary artery pressure—was above normal. And it shot up in response to two triggers of PAH, the neurotransmitter serotonin and the inflammatory cytokine interleukin-6. However, these stimuli didn't spur hypertension in mice that overproduced Ang-1, suggesting that when Ang1 and Tie2 team up, vessels are sheltered.

Tie2 signaling imparts protection in part by blocking death of vessel endothelial cells. Mice with reduced Tie2 activity had increased evidence of apoptosis in their lungs. And blocking apoptosis with a caspase inhibitor prevented the mice from developing disease. The protective effect of this receptor-ligand duo raises questions about the use of Tie2 inhibitors as potential treatments for PAH.