Role of inflammation in pulmonary vascular cell dysfunction in pulmonary arterial hypertension

Title: Role of inflammation in pulmonary vascular cell dysfunction in pulmonary arterial hypertension

Summary

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an arteriopathy of the pre-capillary pulmonary arteries. Heritable pulmonary arterial hypertension is associated with mutations in the bone morphogenetic protein receptor 2(BMPR2) gene. However, only 20% of BMPR2 mutation carriers develop PAH. Furthermore, pulmonary arterial hypertension is associated with inflammation. In this regard, we explored the role of inflammation in vascular cell dysfunction in the presence of impaired BMPRII function in the pathogenesis of PAH.

We first evaluated if mutated BMPR2 status is associated with distinct disease phenotypes in our patient cohort. We found that PAH patients who are BMPR2 mutation carriers are younger at diagnosis, have a more severe haemodynamic profile at diagnosis and are less likely to respond to acute vasodilator testing. 

We then investigated if inflammatory mediators associated with PAH can cause dysfunction of microvascular pulmonary arterial EC and SMC with impaired BMPRII function.

In vascular cells isolated from BMPR2 mutation carriers, we observed that CRP and TNFα increased adhesion capacities of EC and that CRP enhanced PASMC mitogenic activity. We also observed cross-talk between ECs and SMCs in BMPR2 mutation carriers, possibly due to an increase in endothelin production observed in EC.

To further explore potential mechanisms, we knocked down BMPR2 in microvascular EC. We observed that impaired BMPRII function compromised EC barrier function. In addition, we observed that the inflammatory mediator IL-18 increased adhesion capacities of BMPR2 knockdown EC. Finally, we found that an alternative pathway, the p38 MAPK pathway, is activated in BMPR2 knockdown EC and IL-18 further enhances the activation of p38 MAPK.

We conclude that the inflammatory mediators, CRP, TNFα and IL-18, may contribute to vascular cell dysfunction in pulmonary microvascular EC and SMC with impaired BMPRII function. The effects of inflammatory mediators, such as IL-18, could be mediated through the activation of p38 MAPK.