Roles of growth factors on vascular remodeling in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is defined as mean pulmonary arterial pressure at rest ≥25 mmHg. Pulmonary arterial hypertension (PAH) is classified as group 1 of PH and is a progressive and fatal disease of the pulmonary artery. The pathogenesis is sustained pulmonary vasoconstriction and pulmonary vascular remodeling, which cause progressive elevations in pulmonary vascular resistance and pulmonary arterial pressure. Elevated pulmonary arterial pressure leads to right heart failure and finally death. The pulmonary vascular remodeling is triggered by an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt). [Ca²⁺]_cyt is regulated by the stimulation of vasoconstrictors and growth factors though their receptors and ion channels on the plasma membrane. It has been reported that the epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the development of PAH. Upon binding of these growth factors with their specific receptor tyrosine kinases, their receptors activate cytosolic Ca²⁺ signaling and signal transduction cascades to induce cell proliferation, differentiation, and migration. Expressions of some growth factors and their receptors upregulate in PAH patients, which contributes to the formation of vascular remodeling and plexiform lesions in PAH. We have recently found that enhanced Ca²⁺-sensing receptor (CaSR) function is involved the development of PAH and CaSR expression is upregulated by PDGF in pulmonary arterial smooth muscle cells (PASMCs) from idiopathic PAH patients. This review will be discussed the physiological and pathological roles of growth factors in PAH.