Am J Respir Cell Mol Biol. 2011 Aug;45(2):311-22. Epub 2010 Oct 29.

Autocrine FGF2 Signaling Contributes to Altered Endothelial Phenotype in Pulmonary Hypertension.

Tu L, Dewachter L, Gore B, Fadel E, Dartevelle P, Simonneau G, Humbert M, Eddahibi S, Guignabert C.

INSERM U999, Le Plessis Robinson, France; University of Paris-Sud 11, Orsay, France.

Abstract

Rationale - Pulmonary vascular remodeling is key to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We recently reported that fibroblast growth factor-2 (FGF2) is markedly overproduced by pulmonary-endothelial cells (P-ECs) in IPAH, and contributes significantly to smooth muscle hyperplasia and disease progression. Excessive FGF2 expression in malignancy has been shown to exert pathologic effects on tumor cells by both paracrine and autocrine mechanisms. Objectives - Thus, we hypothesized that FGF2-overproduction contributes in an autocrine manner to the abnormal phenotype of P-ECs, characteristic of IPAH. Measurements and Main Results - In distal-pulmonary arteries (PAs) of patients with IPAH, we found increased numbers of proliferating-ECs and decreased numbers of apoptotic-ECs, accompanied with stronger immunoreactivity for the anti-apoptotic molecules, B-Cell Lymphoma (BCL)2 and BCL-extra long (BCL-xL), compared to PAs from control-patients. These in situ observations were replicated in vitro, with cultured P-ECs from IPAH-patients exhibiting increased proliferation and diminished sensitivity to apoptotic induction with marked increases in the anti-apoptotic factors BCL2, BCL-xL, and levels of phosphorylated-extracellular signal-regulated (ERK)1/2 compared to control-P-ECs. Furthermore, IPAH-P-ECs also exhibited increased FGF-receptor-2 expression and an accentuated proliferative and survival response to either conditioned P-EC-media or exogenous-FGF2 treatment. Decreasing FGF2-signaling by RNA-interference normalized both the sensitivity to apoptosis and proliferative potential in the IPAH-P-ECs. Conclusions - Our findings suggest that excessive autocrine release of endothelial-derived FGF2 in IPAH contributes to the acquisition and maintenance of an abnormal EC-phenotype, enhancing proliferation through constitutive activation of ERK1/2 and decreasing apoptosis by increasing BCL2 and BCL-xL.

PMID: 21037114 [PubMed - as supplied by publisher]