Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right
heart failure and ultimately death. Injury to endothelium and consequent
wound repair cascades have been suggested to trigger pulmonary
vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice,
hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of
lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog
resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent
lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and
interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early
inflammation phase. In vitro, HIMF, hRETN, and
IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing
angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the
conditioned medium from hRETN-treated ECs had elevated levels of
endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary
vascular remodeling and right
heart failure in wild-type mice but not in
IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular
inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH.