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Πέμπτη 26 Οκτωβρίου 2017

Endothelial HIF-2{alpha} Contributes to Severe Pulmonary Hypertension by Inducing Endothelial-to-Mesenchymal Transition

Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration contributes to the elevated PVR in patients with IPAH. Here we report that increased HIF-2α in lung vascular endothelial cells (LVEC) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVEC from IPAH patients and PH animals compared with controls. LVEC from IPAH patients had a higher level of HIF-2α than that from normals, while HIF-1α was upregulated in IPAH-PASMC. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), was involved in the enhanced EndMT and upregulated SNAI1/2 in IPAH-LVEC. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1/SNAI2 expression in IPAH-LVEC. Mice with EC-specific knockout (KO) of the PHD2 gene, egln1 (egln1EC–/–), developed severe PH under normoxic conditions; while Snai1/2 and EndMT were increased in LVEC of egln1EC–/– mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or SMC-specific deletion of hif2a, negligibly affected the development of PH. Also, hypoxia (48-72 hrs) increased HIF-1α in normal human PASMC and HIF-2α in normal human LVEC. These data indicate that increased HIF-2α in LVEC plays a pathogenic role in the development of PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and remodeling.



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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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