Deciphering the Counterintuitive Role of Vascular Endothelial Growth Factor Signaling Pathways in Pulmonary Arterial Hypertension

Vascular remodeling and progressive lung vessel obliteration are a histopathological cornerstone for the onset of pulmonary arterial hypertension (PAH). However, the role of vascular endothelial growth factor (VEGF) signaling pathways in the development of histopathological vascular changes in PAH is still incompletely understood. This educational review aims to untangle the opposing and heterogeneous actions of VEGF and the receptors it engages in triggering lung angio-proliferative lesions, driving hemodynamic changes in PAH. A proposed 'VEGF-oriented' approach attempts to untangle some of the contrasting and complementary actions of VEGF in the pathogenesis of the disease. Experimental models provide a cogent explanation for dysfunctional angiogenesis and the paradox of VEGF-receptor-blockade-induced PAH. The multifaced properties of VEGF, whether angiogenic or nonangiogenic, vary depending on the nature of the ligand, receptor-dependent and -independent signaling pathways, and the duration of the ligand-receptor engagement. Further investigation is needed to translate the knowledge acquired to human subjects and to confirm the pathogenic mechanisms surrounding the phenotypic shift to apoptosis-resistant, hyperproliferative cellular subset and the development of angio-obliterative lesions in PAH.