The Mechanism of Action

WHO Group 1 : Pulmonary Arterial Hypertension (PAH)

The initial concept that PAH is caused by mechanisms of vasoconstriction has been expanded over the last decades to a more complex picture in which multiple genetic, epigenetic, and environmental mechanisms lead to pulmonary vascular remodeling.  In some regards, PAH may even be considered as a pseudo-malignant disease with similar features to cancer.  It is now accepted that curative therapeutic approaches for PAH must address vascular remodeling, by inhibiting proliferative and activating anti-proliferative mechanisms.

Many experimental data support the concept that platelet derived growth factor (PDGF) pathways play an important role in the pulmonary vascular remodeling process responsible for the progression of PAH. PDGF is known to induce proliferation of pulmonary arterial endothelial and smooth muscle cells and reversal of experimental pulmonary hypertension in animal models was demonstrated with imatinib through PDGF inhibition.

Imatinib is a tyrosine kinase inhibitor of PDGF, c-KIT, and BCR-ABL which are growth factors that regulate endothelial and vascular smooth muscle cell proliferation in PAH. These growth factors are highly expressed in patients with PAH and contribute to disease progression. 

Inhibition of PDGF-induced pulmonary vascular proliferation with imatinib supports the therapeutic role of PDGF inhibition as a novel approach in PAH. Because pulmonary arterial proliferation and migration are believed to be a major contributor to pulmonary vascular remodeling, these findings plead in favor of the potential relevance of PDGF inhibition in the treatment of human PAH.