Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition

Haiyang Tang, Aleksandra Babicheva, Kimberly M. McDermott, Yali Gu, Ramon J. Ayon, Shanshan Song, Ziyi Wang, Akash Gupta, Tong Zhou, Xutong Sun, Swetaleena Dash, Zilu Wang, Angela Balistrieri, Qiuyu Zheng, Arlette G. Cordery, Ankit A. Desai, Franz Rischard, Zain Khalpey, Jian Wang, Stephen Matthew BlackJoe G.N. Garcia, Ayako Makino, Jason X.J. Yuan

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) 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 LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1 E C -/- ), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1 E C -/- 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 smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48–72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.

Original languageEnglish (US)
Pages (from-to)L256-L275
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume314
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Pulmonary Hypertension
Endothelial Cells
Lung
Prolyl Hydroxylases
Smooth Muscle Myocytes
Hypoxia-Inducible Factor-Proline Dioxygenases
endothelial PAS domain-containing protein 1
Cell Hypoxia
Vascular Resistance
Small Interfering RNA
Genes
Blood Vessels
Familial Primary Pulmonary Hypertension
Proteins
Down-Regulation

Keywords

  • Endothelial cell
  • Intimal lesion
  • Prolyl hydroxylase domain-containing protein
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. / Tang, Haiyang; Babicheva, Aleksandra; McDermott, Kimberly M.; Gu, Yali; Ayon, Ramon J.; Song, Shanshan; Wang, Ziyi; Gupta, Akash; Zhou, Tong; Sun, Xutong; Dash, Swetaleena; Wang, Zilu; Balistrieri, Angela; Zheng, Qiuyu; Cordery, Arlette G.; Desai, Ankit A.; Rischard, Franz; Khalpey, Zain; Wang, Jian; Black, Stephen Matthew; Garcia, Joe G.N.; Makino, Ayako; Yuan, Jason X.J.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 314, No. 2, 01.02.2018, p. L256-L275.

Research output: Contribution to journalArticle

Tang, H, Babicheva, A, McDermott, KM, Gu, Y, Ayon, RJ, Song, S, Wang, Z, Gupta, A, Zhou, T, Sun, X, Dash, S, Wang, Z, Balistrieri, A, Zheng, Q, Cordery, AG, Desai, AA, Rischard, F, Khalpey, Z, Wang, J, Black, SM, Garcia, JGN, Makino, A & Yuan, JXJ 2018, 'Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 314, no. 2, pp. L256-L275. https://doi.org/10.1152/ajplung.00096.2017
Tang, Haiyang ; Babicheva, Aleksandra ; McDermott, Kimberly M. ; Gu, Yali ; Ayon, Ramon J. ; Song, Shanshan ; Wang, Ziyi ; Gupta, Akash ; Zhou, Tong ; Sun, Xutong ; Dash, Swetaleena ; Wang, Zilu ; Balistrieri, Angela ; Zheng, Qiuyu ; Cordery, Arlette G. ; Desai, Ankit A. ; Rischard, Franz ; Khalpey, Zain ; Wang, Jian ; Black, Stephen Matthew ; Garcia, Joe G.N. ; Makino, Ayako ; Yuan, Jason X.J. / Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2018 ; Vol. 314, No. 2. pp. L256-L275.
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T1 - Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition

AU - Tang, Haiyang

AU - Babicheva, Aleksandra

AU - McDermott, Kimberly M.

AU - Gu, Yali

AU - Ayon, Ramon J.

AU - Song, Shanshan

AU - Wang, Ziyi

AU - Gupta, Akash

AU - Zhou, Tong

AU - Sun, Xutong

AU - Dash, Swetaleena

AU - Wang, Zilu

AU - Balistrieri, Angela

AU - Zheng, Qiuyu

AU - Cordery, Arlette G.

AU - Desai, Ankit A.

AU - Rischard, Franz

AU - Khalpey, Zain

AU - Wang, Jian

AU - Black, Stephen Matthew

AU - Garcia, Joe G.N.

AU - Makino, Ayako

AU - Yuan, Jason X.J.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) 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 LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1 E C -/- ), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1 E C -/- 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 smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48–72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.

AB - Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) 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 LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1 E C -/- ), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1 E C -/- 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 smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48–72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.

KW - Endothelial cell

KW - Intimal lesion

KW - Prolyl hydroxylase domain-containing protein

KW - Pulmonary arterial hypertension

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