PDGF signaling in pulmonary arterial hypertension

Abstract

The pathobiology of pulmonary arterial hypertension (PAH) includes endothelial cell dysfunction and proliferation and migration of VSMCs. As PDGF has been implicated in these processes, Schermuly et al. hypothesized that altered PDGF signaling may be involved in the vascular remodeling observed in PAH. To explore this notion further, the authors evaluated the effects of the PDGF receptor inhibitor STI571 in 2 different animal models of pulmonary hypertension. In both models, after development of pulmonary vascular disease, administration of STI571 reversed pulmonary vascular changes. These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for PAH patients.

Figure 1

Cellular and molecular pathobiology of pulmonary vascular remodeling in PAH. ET-1, endothelin 1; 5-HT, serotonin; Kv, potassium channel; PGI₂, prostacyclin; TXA₂, thromboxane A₂; VIP, vasoactive intestinal peptide.

Figure 2

Schematic representation of pulmonary vascular remodeling in the small pulmonary arteries in PAH. (A) PDGF receptor (PDGFR) expression and phosphorylation (P) in pulmonary arteries are increased in PAH, which activates downstream signaling pathways that promote the abnormal proliferation and migration of VSMCs as well as the formation of a layer of microfibroblasts and extracellular matrix (termed the neointima) between the internal elastic lamina and the endothelium. These changes underlie the structural and functional abnormalities in the vessel wall that lead to pulmonary vascular disease. (B) In this issue of the JCI, Schermuly et al. demonstrate that administration of the PDGF receptor antagonist STI571 induces a reversal of the pulmonary vascular remodeling in 2 different animal models of pulmonary hypertension. STI571 prevents phosphorylation of the PDGF receptor and consequently suppresses activation of downstream signaling pathways associated with PAH.