Autocrine Fibroblast Growth Factor-2 Signaling Contributes to Altered Endothelial Phenotype in Pulmonary Hypertension
Autocrine Fibroblast Growth Factor-2 Signaling Contributes to Altered Endothelial Phenotype in Pulmonary Hypertension
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DOI：
10.1165/rcmb.2010-0317oc
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发表时间：
2011-08-01
影响因子：
6.4
通讯作者：
Guignabert, Christophe
中科院分区：
文献类型：
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作者：
Ly Tu;Dewachter, Laurence;Guignabert, Christophe
肺血管重构是特发性肺动脉高压（IPAH）发病的关键。我们最近报道了成纤维细胞生长因子（FGF）2在IPAH中由肺内皮细胞（P-ECs）明显过量产生，并在平滑肌增生和疾病进展中起重要作用。恶性肿瘤中过量的FGF2表达通过旁分泌和自分泌机制对肿瘤细胞产生病理作用。我们假设FGF2的过量产生以自分泌的方式导致了pecs的异常表型，这是IPAH的特征。在IPAH患者的远端肺动脉（PAs）中，我们发现增生的ECs数量增加，凋亡的ECs数量减少，与对照患者的PAs相比，对抗凋亡分子，b细胞淋巴瘤（BCL）2和BCL超长（BCL- xl）具有更强的免疫反应性。这些原位观察结果在体外得到了重复，与对照P-ECs相比，IPAH患者培养的P-ECs增殖增加，对凋亡诱导的敏感性降低，抗凋亡因子BCL2和BCL-xL以及磷酸化的细胞外信号调节（ERK）1/2水平明显增加。IPAH P-EC也表现出FGF2表达增加，对条件P-EC培养基或外源性FGF2处理的增殖和生存反应增强。通过RNA干扰降低IPAH P-ECs中FGF2信号通路对凋亡和增殖潜能的正常化敏感性。我们的研究结果表明，IPAH中内皮源性FGF2的过度自分泌释放有助于获得和维持异常EC表型，通过ERK1/2的组成性激活促进增殖，并通过增加BCL2和BCL-xL来减少凋亡。
Pulmonary vascular remodeling is key to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We recently reported that fibroblast growth factor (FGF)2 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 exerts pathologic effects on tumor cells by paracrine and autocrine mechanisms. We hypothesized that FGF2 overproduction contributes in an autocrine manner to the abnormal phenotype of P-ECs, characteristic of IPAH. 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 antiapoptotic molecules, B-cell lymphoma (BCL)2, and BCL extra long (BCL-xL) compared with PAs from control patients. These in situ observations were replicated in vitro, with cultured P-ECs from patients IPAH exhibiting increased proliferation and diminished sensitivity to apoptotic induction with marked increases in the antiapoptotic factors BCL2 and BCL-xL and levels of phosphorylated extracellular signal-regulated (ERK)1/2 compared with control P-ECs. IPAH P-ECs also exhibited increased FGF2 expression and an accentuated proliferative and survival response to conditioned P-EC media or exogenous FGF2 treatment. Decreasing FGF2 signaling by RNA interference normalized sensitivity to apoptosis and proliferative potential in the IPAH P-ECs. 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.